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Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Reactive Oxygen Species (ROS)-Based Nanomedicine Bowen Yang,†,‡ Yu Chen,*,† and Jianlin Shi*,† †

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State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China ‡ University of Chinese Academy of Sciences, Beijing 100049, P. R. China ABSTRACT: Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms. The intrinsic biochemical properties of ROS, which underlie the mechanisms necessary for the growth, fitness, or aging of living organisms, have been driving researchers to take full advantage of these active chemical species for contributing to medical advances. Thanks to the remarkable advances in nanotechnology, great varieties of nanomaterials with unique ROS-regulating properties have been explored to guide the temporospatial dynamic behaviors of ROS in biological milieu, which contributes to the emergence of a new-generation therapeutic methodology, i.e., nanomaterial-guided in vivo ROS evolution for therapy. The interdependent relationship between ROS and their corresponding chemistry, biology, and nanotherapy leads us to propose the concept of “ROS science”, which is believed to be an emerging scientific discipline that studies the chemical mechanisms, biological effects, and nanotherapeutic applications of ROS. In this review, state-of-art studies concerning recent progresses on ROS-based nanotherapies have been summarized in detail, with an emphasis on underlying material chemistry of nanomaterials by which ROS are generated or scavenged for improved therapeutic outcomes. Furthermore, key scientific issues in the evolution of ROS-based cross-disciplinary fields have also been discussed, aiming to unlock the innate powers of ROS for optimized therapeutic efficacies. We expect that our demonstration on this evolving field will be beneficial to the further development of ROS-based fundamental researches and clinical applications.

CONTENTS 1. Introduction 1.1. Definition of “ROS Science” 1.1.1. ROS Chemistry 1.1.2. ROS Biology 1.1.3. ROS Nanotechnology 1.2. Status Quo of ROS Science in Nanomedicine 1.3. Scope of This Review 2. Material Chemistry of ROS-Based Nanoplatforms 2.1. ROS-Generating Nanoplatforms 2.2. ROS-Scavenging Nanoplatforms 2.3. Related Analytical Techniques 3. ROS-Based Cancer Nanotherapy 3.1. Photodynamic Therapy (PDT) 3.1.1. Nanomedicine-Facilitated Photoactivation 3.1.2. Deep PDT by Different Excitation Sources 3.1.3. Recent Advanced Strategies to Augment PDT 3.2. Sonodynamic Therapy (SDT) 3.2.1. Organic Nanosonosensitizer-Augmented SDT 3.2.2. Inorganic Nanosonosensitizer-Augmented SDT 3.2.3. Nanotechnology-Augmented but Sonosensitizer-free SDT 3.3. Radiation Therapy (RT)

© XXXX American Chemical Society

3.3.1. Radiosensitization of Tumor by Nanomaterials 3.3.2. RT Enhancement by Tumor Microenvironment (TME) Modulation 3.3.3. Radiation Protection by ROS Scavenger 3.4. Chemodynamic Therapy (CDT) 3.4.1. Catalytic ROS Generation by Fenton or Fenton-like Reactions 3.4.2. CDT Enhancement by Sequential Catalytic Reactions 3.4.3. Chemodynamic ROS Generation by Other Mechanisms 3.5. Controlled Drug Release (CDR) 3.5.1. CDR Directly Activated by Endogenous Intratumoral H2O2 3.5.2. CDR by Endogenous H2O2 Decomposition and O2 Generation 3.5.3. CDR by 1O2 Generation under Exogenous Activation of Physical Triggers 3.6. Synergistic Therapy 3.6.1. PDT-Based Synergistic Therapy 3.6.2. SDT-Based Synergistic Therapy 3.6.3. RT-Based Synergistic Therapy 3.6.4. CDT-Based Synergistic Therapy

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DOI: 10.1021/acs.chemrev.8b00626 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 4. ROS-Related Nanotherapy for Other Pathological Abnormalities 4.1. Brain Diseases 4.1.1. ROS-Responsive Nanoplatforms To Facilitate Neuroprotective Drug Release 4.1.2. Catalytic Depletion of Excess ROS by Enzymatic Reactions 4.1.3. “Copper Chelation” Strategy To Assist ROS Decomposition 4.2. Inflammatory Diseases 4.2.1. ROS Depletion by Organic/Inorganic Antioxidants 4.2.2. Anti-inflammatory Nanoreactors Responsive to Endogenous ROS 4.2.3. Anti-inflammatory Nanoreactors Responsive to Exogenous Stimulus 4.3. Cardiovascular Diseases 4.3.1. Nanoplatforms Facilitate Cell Adhesion in ROS Microenvironment 4.3.2. Therapeutic Platforms Scavenge Excessive ROS To Augment Heart Repair 4.3.3. Genetic Pathways Activate the Antioxidant Response 4.4. Bacterial infection 4.4.1. Chemo-Driven ROS Generation by Nanozymes 4.4.2. Photodriven ROS Generation by Semiconductors 4.4.3. Electric-Driven ROS Generation by Electrochemiluminescence 4.5. Other Diseases 5. Further Discussions on ROS−Material Interactions: Biodegradability 6. Pharmacokinetics and Biodistribution of ROSBased Nanoplatforms 7. Conclusions and Outlook Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations References

Review

reduction of oxygen.2 It mainly includes superoxide anion (O2•−), hydrogen peroxide (H2O2), singlet oxygen (1O2), and hydroxyl radical (•OH).3−8 These chemical species participate in phenomena that traverse all of biology, playing an essential role in regulating various physiological functions of living organisms.9 The intrinsic biochemical properties of ROS underlie the mechanisms necessary for the development of living organisms, while overproduction of ROS leads to oxidative stress that is implicated in numbers of diseases such as cancer,10 neurodegenerative diseases,11 inflammation,12 etc. The past century has witnessed the joint efforts that chemists and biologists have made to unveil these chemical species and their underlying redox chemistry, which also benefits us to conceive feasible ROS-related therapeutic approaches. However, on account of the transient and reactive nature of ROS, as well as the unpredictability of related biological processes, a major question for ROS-based therapeutics is how we can finely regulate ROS concentrations within an expected threshold, thus to initiate therapeutic effects for making medical advances? Thanks to the marked breakthroughs in the field of nanotechnology, especially in nanochemistry and nanofabrication technologies, great varieties of nanomaterials with unique ROS-regulating properties have been fabricated to favor ROSinvolved chemical reactions for extensive biomedical applications. Such a nanoenabled integration of material science with ROS chemistry and biology has catalyzed the emergence of a next-generation therapeutic methodology: we can first tune the biochemical properties of ROS-based nanomedicine based on the nanosynthetic chemistry, thus to regulate the generation, evolution, and depletion processes of ROS in different biological scenarios, which finally benefits the ROS-based therapeutic outcomes. On account of the predictability of chemical synthesis for the fabrication of ROS-based nanoplatforms, this strategy can be highly feasible. A further consideration is the phenomenon that the naissance of this therapeutic strategy facilitates the gradual fusion among different research fields. In the past century, the rapid growth of ROS-related researches has greatly enriched our knowledge on the biochemical properties of ROS and ROS-related artificial materials, as manifested in the following three aspects: (1) chemists investigate the ROS-involved reaction mechanisms such as pathways and kinetics; (2) biologists unveil the biological processes of ROS and their physiological roles in organisms; (3) materials scientists demonstrate the features of nanodimensional materials in guiding the temporospatial dynamic behaviors of ROS. The interdependent relationship among ROS chemistry, biology, and nanotechnology leads us to propose the concept of “ROS science”, which is believed to be an emerging discipline that studies ROS-based chemical mechanisms, biological effects, and nanomaterials. As a cross-disciplinary research field, ROS science elucidates the fundamental principles of its three subdisciplines: ROS chemistry, ROS biology, and ROS nanotechnology, seeks to disclose the underlying material chemistry of ROS-regulating nanomaterials, and considers rational therapeutic strategies based on these tailored nanoplatforms, aiming to contribute to the further development of various therapeutic modalities (Figure 1). It draws from chemistry, biology, material science, physics, pathophysiology, pharmacology, oncology, etc., displaying the intrinsic crossdisciplinary nature of ROS science as proposed herein. The core of ROS science can be described as follows: based on a comprehensive understanding of the chemical/biological

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1. INTRODUCTION 1.1. Definition of “ROS Science”

As Professor Jean-Marie Lehn, 1987 Nobel Prize winner in chemistry, once stated in his monograph: “the chemist finds inspiration in the ingenuity of biological events and encouragement in the demonstration that such high efficiencies, selectivities, and rates can indeed be attained.”1 This motto guides scientists to link chemistry with biology to promote social progress. For example, chemistry and biology can contribute, in an integrated manner, to the emergence of numerous therapeutic approaches, armed with the better understanding on how chemical species affect various physiological activities and how we can unlock the innate powers of these chemical species for ultimate therapeutic aims. Reactive oxygen species (ROS) is a collective term that describes the chemical species formed upon incomplete B


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Figure 1. ROS science and material chemistry of nanomedicine.

1894, when Fenton reported strong oxidation characteristics of H2O2 in the presence of Fe2+,13 ROS chemistry had entered into its era, and since then, great numbers of researches have successfully demonstrated the chemical intercorrelations among ROS and nature, materials, as well as biological milieu. The deeper elucidation of ROS chemistry benefits us to trace the origin of ROS. Nature synthesizes these ROS omnipresent in different environmental compartments via varied mechanisms; for example, in the upper troposphere, •OH radicals can be produced by the photolysis of gaseous ozone (Figure 3b).14 Materials can also guide ROS generation via various catalytic reactions, to favor the transitions of exogenous energy to the endogenous chemical energy of ROS. Year 1972 marked the booming growth of photocatalytic chemistry when Fujishima and Honda reported that semiconducting TiO2 could serve as a photocatalyst for water-splitting,15 and the involved •OH

properties of ROS, as well as the nanobio interactions of ROSrelated nanomaterials, we can design and fabricate newgeneration nanosystems with unique ROS generation/depletion features to exert therapeutic effects, finally to meet the ever-stringent demands of clinical applications (Figure 2). ROS science provides a general guideline to study the principles of ROS-related chemical and biological processes and inspires novel strategies to tailor advanced nanomedicines. To provide a more comprehensive picture of the new paradigm of “ROS science”, we will further discuss its three subdisciplines: ROS chemistry, ROS biology, and ROS nanotechnology, in the following sections of this review. 1.1.1. ROS Chemistry. Over a century’s collective efforts of chemists have pushed forward the sustained development of ROS chemistry to uncover the unique chemical characteristics of these chemical species (Figure 3a). Dating back to the year C


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Figure 2. ROS-based nanomedicine for various applications. The abundant material chemistry endows nanomedicines with unique ROS generation/ depletion properties for the treatment of various pathological disfunctions (such as cancer, neurodegenerative diseases, bacterial infection, etc.). Analytical technologies have also been developed to evaluate the ROS-regulating efficiency of these therapeutic platforms.

ROS radicals can be ranked based on the one-electron reduction potential because the activation energy is rather low.22 Such a physicochemical parameter can also provide feasible tools to predict the orientation of ROS-related reactions. For example, in pH = 7 environment, E0 (O2•−, 2H+/H2O2) > E0 (H2O2, H+/•OH);22 thus, the reduction of O2•− to H2O2 is more favorable than the reduction of H2O2 to • OH.3 Comparatively, for two-electron nonradical ROS, although reduction potentials also determine their oxidative strengths, kinetic factors are actually more dominant in determining their reactivity. Higher activation energy corresponds to lower reaction rate.22 Reactivity of ROS determines their reaction specificity in a biological environment. Once ROS are generated at a given location, they can mediate a diverse array of redox modifications on biomolecules in a temporal and sequencespecific manner (Figure 3d).21,23 •OH and 1O2 present indiscriminate reactivities due to their strong oxidizing properties, whereas either O2•− or H2O2 has its preferred biological targets.2 Such a preference can be well-exemplified by two early observations on Escherichia coli (E. coli) for ROS discrimination. The first example indicates the specific reactivity of O2•− with iron−sulfur clusters ([Fe−S] clusters),2,24 which favors the release of H2O2 and Fe2+ responsible for O2•− mediated toxicity, such as highly active •OH generation by Fenton chemistry.25 The other paradigm provides us with a mechanistic demonstration on the high reactivity of H2O2 with cysteine (Cys) residues, which is the fundamental chemical mechanism for cellular signaling.26 It is noteworthy that the biochemistry of 1O2 has been less investigated because it is commonly generated via exogenous photochemical reactions rather than endogenous biological reactions. The above discussion on the reaction characteristics of ROS is based on the assumption that these reactions take place in a

generating processes have been gradually recognized and elucidated in the next four decades (Figure 3c).16 The exploration of highly efficient ROS-generating catalysts not only benefits the relevant industrial sectors but also favors many medical applications for disease treatment.17 Further discussions on the mechanisms of material-assisted ROSgeneration will be provided in the following sections. Another key ROS source is biological systems. Cells can produce ROS at different subcellular locations, of which a major one is mitochondria. Electrons escaped from the mitochondrial respiratory chain can react with O2 molecules to generate O2•− (primary ROS), which can be further converted to H2O2, •OH, ClO−, etc. (secondary ROS) via various catalytic reactions.18 In some cancer cells, ROS can be produced by the activation of seven isoforms of NADPH oxidase (NOX) complexes located in cytomembranes.19,20 Flavoenzyme ERO1 in the endoplasmic reticulum (ER) was also demonstrated to utilize O2 as a twoelectron acceptor to generate one equivalent of H2O2, providing a strong ROS flux in this subcellular region.21 Moreover, xanthine oxidase (XO), lipoxygenases, cyclooxygenases, and metal ions (such as Fe2+ and Cu2+) can also participate in catalytic ROS generation.9 High reactivity is the most prominent feature of ROS. These chemical species exist far from the equilibrium state in solvent environment, and various ROS-involved reactions such as oxidation, reduction, or dismutation may take place. Based on the reaction mechanisms, ROS can be further divided into oneelectron (radical species, such as O2•− and •OH) and twoelectron (nonradical species, such as H2O2) oxidants, and their oxidative activities are different from each other. It is essential to identify and differentiate the oxidative strength of individual ROS for a better understanding of the reaction mechanisms, i.e., which type of oxidant will be involved in a particular reaction process. The oxidizing capabilities of one-electron D


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Figure 3. ROS chemistry. (a) Primary subtypes of ROS and their generation/transformation processes, which reveal the interdependent relationships among these biochemical oxidants. The colors marked in the box indicate the reactivities of individual ROS. Green: relatively low reactivity; yellow: limited reactivity; orange: moderate reactivity; red: high reactivity. Phox, phagocyte oxidase; MPO, myeloperoxidase; SOD, superoxide dismutase. Reprinted with permission from ref 20. Copyright 2004 Nature Publishing Group. (b) ROS chemistry in nature. Photochemical reactions facilitate ROS generation in various natural environments, such as atmosphere, seawater, and indoor space. VOC, volatile organic compound; SOA, secondary organic aerosol. Reprinted with permission from ref 7. Copyright 2015 American Chemical Society. (c) ROS chemistry with materials. Proposed photocatalytic reaction paths at bridged (c1) or terminal (c2) OH sites of TiO2. Reprinted with permission from ref 16. Copyright 2016 American Chemical Society. (d) ROS chemistry in biology. The diverse chemical properties of ROS make them react with their preferred biological targets. Reprinted with permission from ref 2. Copyright 2007 Nature Publishing Group.

1.1.2. ROS Biology. Warburg’s 1908 observation is the first milestone of ROS biology, which revealed the increased oxygen consumption in sea urchin eggs after fertilization (H2O2producing respiratory burst).27 Currently, there is an increasing number of areas in ROS biology where discrete biochemical and cellular investigations are complementary with each other, providing systematic explanations on the physiological roles of ROS.9 ROS can serve as intracellular signaling molecules, a function that has been extensively documented but remains controversial.2 •OH and 1O2 have relatively short diffusion distances and can only exist in compartmentalized spaces. Therefore, they are not capable of functioning in cellular redox signaling pathways. In addition, the instability of O2•− and its inability to diffuse across membranes also make this type of ROS a poor signaling molecule.2 Comparatively, the mild reactivity, high specificity, strong diffusibility, and membrane permeability of H2O2 molecules make them competent to serve as a critical messenger for intercellular crosstalk. Cys residues are the most frequent target for H2O2-mediated signaling pathways, which participate in the regulation of numerous physiological activities (Figure 4).

homogeneous solution and are not affected by steric hindrance. In fact, all organismal subunits at diverse stratifications (e.g., cells, tissues, organs, and the whole organism) are heterogeneous systems with temporospatially dynamic architectures. Due to the transient and reactive nature of ROS, these redox reactions proceed in a site-localized manner. Almost all ROS travel within a relative shorter range compared to the diameter of the cell, except H2O2 (around 1.5 mm).22 Therefore, the compartmentalization of ROS should be taken into consideration when we investigate the ROS-involved reactions in biological milieu. Some redox reactions, although theoretically possible, will not be physiologically relevant because of temporospatial limitations.22 The reactivity, specificity, and diffusibility are three key reaction characteristics of ROS chemistry collectively determining the biochemical behaviors of these active species in a physiological environment. Recent advances in ROS chemistry benefit researchers to acquire an ever-clear understanding on the complicated and mysterious chemical processes, providing advanced tools to further explore ROS biology, such as oxidative stress and consequent pathology. E


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Figure 4. ROS mediate intracellular signaling for physiological regulation. Specific ligand−receptor binding enables the generation of O2•−, which can be converted into H2O2 through a disproportionation reaction. Small amounts of H2O2 are capable of diffusing back into the cell to interact with specific redox-sensitive target protein for intracellular signaling (dashed arrow in the schematic illustration). GDP, guanosine diphosphate; GTP, guanosine triphosphate; SOH, sulphenic acid; SH, thiol. Reprinted with permission from ref 28. Copyright 2014 Nature Publishing Group.

Figure 5. ROS-related cellular redox homeostasis. Mitochondrial electron transport chain (Mito-ETC), ER system, and NOX complex are the major reaction sites for intracellular ROS generation. To prevent the harmful effects of excessive ROS, various ROS-scavenging enzymes are also available in cells to participate in the downregulation of oxidative stress, thus keeping ROS content within normal ranges. GR, glutathione reductase; GPX, glutathione peroxidase; GRXo, oxidized glutaredoxin; GRXr, reduced glutaredoxin; TRXo, oxidized thioredoxin; TRXr, reduced thioredoxin; GSHr, reduced glutathione; GSSG, oxidized glutathione. Reprinted with permission from ref 10. Copyright 2009 Nature Publishing Group.

report in 2003 first demonstrated that NOX could facilitate plant cell growth by promoting ROS generation and activating Ca2+ channels.29 At the molecular level, Kim et al. also

Observations regarding ROS-mediated intracellular signaling are gradually shaping our understanding on a range of topics, such as cell biology and circadian rhythm.9,21,28 Foreman’s F


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(e.g., oncogenes activation, aberrant metabolism, and functional p53 loss), and extrinsic biological factors in tumor environment (e.g., hypoxia and nutrients imbalance), facilitate excessive ROS production and affect cellular redox homeostasis.56 In reverse, compelling evidence also suggests that the elevation of ROS levels in cancer cells also favors the acquisition of the hallmarks of cancer. At moderate redox status, ROS contribute to the tumorigenesis by participating in pro-oncogenic signaling pathways or promoting genomic DNA mutation.56 For example, ROS can activate redox-sensitive transcription factors to regulate the expression of specific proteins that are involved in proliferation, immortalization, and metastasis, favoring the survival of cancer cells.57,58 Moreover, it has also been proved that, in cancer cells, mitochondrial ROS is able to amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations, and thus to facilitate cancer cell metastasis.59 Although recent advances in ROS biology have enabled researchers to gradually uncover the mechanisms of ROSrelated physiology and pathology, however, further in-depth elucidations on the cellular location, signaling pathways, and regulatory targets of ROS are still greatly necessary to acquire a more comprehensive conceptual picture on the interplay between ROS signaling and ROS homeostasis. 1.1.3. ROS Nanotechnology. Nanotechnology stimulates the next wave of technological innovations in ROS science, which has promoted the emergence of numerous multifunctional nanomaterials with unique ROS generation, transition, or depletion functions. Based on the ROS-regulating chemistry of these nanomaterials, as well as the intrinsic biology of asregulated ROS, nanomaterial-based redox-regulation therapeutic strategies come into being: these materials can act as exogenous interventions to participate in the modulation of cellular redox status, and thus to exert therapeutic effects on various ROS-related pathological abnormities, further facilitating the development of ROS-based nanotherapeutic modalities. ROS nanotechnology is based on the intrinsic biophysical features (e.g., thermodynamics, 2D surface topography, and 3D stereoscopic geometry) and biochemical characteristics (e.g., interfacial reactivity and enzymatic interaction) of nanomaterials, which guides the dynamic evolution of ROS in specific time periods and at specific biological locations, thus bridging ROS chemistry, ROS biology, and downstream material chemistry of ROS-based nanomedicine. ROS nanotechnology concentrates on the ROS-related nanochem interface (ROS generation, ROS transition, and ROS scavenging) for enhanced reaction efficiencies and ROS-related nanobio interactions (bioavailability, biodegradability, and biocompatibility) for better therapeutic outcomes, contributing to the gradual establishment of a new subdiscipline of ROS science. Synthetic chemists extract bulk materials from nature and create novel nanomaterials via dimension transition from bulk to micro to nano (top-down), or from atom to molecule to nano (bottom-up). Such a size-evolution facilitates the fabrication of nanomaterials with diversified microcosmic architectures, i.e., 0D nanoparticles, 1D nanowires, 2D nanosheets, and 3D nanoformulations. Here, synthetic chemists are the architect, while nanomaterials are their crafts. Nevertheless, why do we focus on nano rather than micro or other dimensions for the design of ROS-based therapeutic medicines? The answers are the size effect and surface area/ volume differences.

evidenced that NOX-derived H2O2 could mediate Slingshot-1L activation to modulate cytoskeleton organization, thus regulating cell migration.30 Moreover, Niethammer et al. also discovered that in wounded zebrafish larvae, endothelial cells near injured tissue could activate the dual oxidase to create a tissue-scale gradient of H2O2, facilitating the recruitment of leukocytes to the wound.31 In addition to cell biology, the other fascinating research area is circadian rhythm. Red blood cells (RBCs) have been demonstrated to undergo 24-h redox cycles of peroxiredoxin proteins between their reduced and oxidized forms, and such redox cycles can persist for many days.32 Although its molecular basis has not been fully identified, the correlation between the fluctuations in adenosine triphosphate (ATP) and NADPH reveals the role of ROS in regulating circadian rhythm.21 ROS is a double-edged sword. Although a moderate concentration of ROS can act as second messenger for physiological regulation, however, excessive ROS may overwhelm the antioxidant capacity of cell and trigger cell death.10 Cellular redox homeostasis is ensured by maintaining the balance between ROS generation and elimination (Figure 5). Endogenous biological ROS generators include NOXs,19,20 hypoxia,33−35 metabolic defects,36 ER stress,37 lipoxygenases,9 cyclooxygenases,9 cytochrome (Cyt) P450 enzymes,38 and redox-cycling metals (e.g., Fe2+ and Cu2+),21 while intracellular antioxidants such as superoxide dismutase (SOD),22 catalase (CAT),38 nuclear factor erythroid 2-related factor 2 (NRF2),39 glutathione (GSH),40 NADPH,41 and many dietary antioxidant compounds (e.g., vitamin C, vitamin E, selenium, etc.)42 can scavenge these generated ROS for maintaining cellular redox homeostasis. Ensuring the redox homeostasis is of great significance in maintaining the regular physiological functions and reducing the incidence of diseases. If the unbalanced redox status becomes beyond the cellular tolerability thresholds, many pathological dysfunctions will occur, such as aging and tumorigenesis. Mounting evidence indicated that, oxidative stress is a key factor in leading to the aging of biological entities.43−46 At the cellular level, an early observation has demonstrated that the increased cellular ROS concentration could induce a senescence-like state in human diploid fibroblasts.47 At the whole organismal scale, cardiovascular,48 ophthalmological,49 and neurological50 researches have demonstrated the strong correlations between ROS disequilibrium and senescence, which has gradually uncovered the pathogenesis of various senescence-induced pathological abnormalities, such as atherosclerosis,51 cataracts,49 and neurodegenerative diseases.11,52 The incidences of these diseases increase exponentially with age, which has drawn broad attention worldwide. Comparatively, moderately excessive levels of ROS within the threshold of cellular redox homeostasis may oppositely extend the lifespan of living species. It has been recently demonstrated that the exposure to low-dose oxidants will increase the lifetime of drosophila.53 Many types of cancer cells are characteristic of increased aerobic glycolysis (termed as the “Warburg effect”) and elevated ROS levels.10,54 The relevance between ROS and carcinogenesis was first demonstrated in 1981, when insulin was identified to promote intracellular H2O2 production and facilitate tumor cell proliferation.55 However, until now, the causal relationship between the elevated ROS levels and tumorigenesis has remained controversial. It is now widely accepted that the intrinsic biochemical factors in cancer cells G


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Figure 6. Unique size effect of materials in nano dimension. Evaluations on the relationship between the size of nanoparticulate TiO2 and their efficacy (a), transparency (b), ROS-related nanotoxicity (c), and aggregative indicator (d). It can be concluded that the unique size effect of ROSbased nanomaterials plays a vital role in determining their physicochemical properties and then to regulate the subsequent physiological responses in the biological systems. Reprinted with permission from ref 66. Copyright 2010 Nature Publishing Group.

From the perspective of nanochem interface, recent advances in nanosynthetic chemistry and nanocatalytic chemistry have provided feasible tools to regulate the reaction characteristics of ROS-based nanomedicines, by (1) precise modulation of their topographic features with increased number of active sites localized on the surface and (2) integration of them with exogenous functional materials to enhance the activities, selectivities, and versatilities of these nanoparticles in biological systems. Synthetic chemists use their creativities to tailor ROSbased nanomedicines with enhanced ROS-generating/scavenging efficiencies, thus to modulate the reaction processes and benefit the downstream therapeutic outcomes. For example, heterogeneous nanocomposite catalysts with synergetic catalytic ROS-generating effects can be applied for cancer therapeutics by in situ generation of ROS through enzymatic reactions.17,61−63 From the standpoint of nanobio interactions, we are supposed to have a more comprehensive insight into the systematic biological effects of nanomedicines. The large surface area of nanomaterials leads to the strong adsorption of various biomolecules (e.g., phospholipid, protein and DNA) in biological systems to reduce their excessive surface energy.64 The nanoparticle−biomacromolecule interactions can further influence downstream nanoparticle−cell interplays, such as

When the sizes of materials are decreased to nanoscale, they will display abundant unique characteristics that are not owned by their bulk counterparts. For example, crystallographic alterations (e.g., lattice deformation, atoms rearrangements, or morphological changes) often occur on the surface of inorganic nanoparticles below 20−30 nm in size,60 which can further regulate the interfacial reaction kinetics mediated on the surface of nanoparticles (such as the kinetics of ROS generation/ depletion).60 Moreover, the large specific surface areas of nanomaterials provide abundant anchoring points for ambient reactive molecules, further improving their chemical reactivities, while the small volumes of nanomaterials facilitate the tissue penetration, cellular uptake, and intracellular transport of these nanosystems. Therefore, the integration of extrinsic properties (topographical and geometrical features, such as small particle size, small volume, and large specific surface area) and intrinsic characteristics (dimension transition-enabled transformation in physical and chemical features) endow nanodimensional materials with superior ROS-regulating performances and in vivo behaviors for numerous therapeutic applications. Here, “ROS-based nanomedicine” is proposed as the definition of these ROS-regulating nanomaterials, which is not only the kernel of ROS nanotechnology but also the evolving research field in ROS science. H


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Figure 7. Snapshot of historical trends in ROS science over a century.

nanoparticles-mediated cellular substructural alterations and biochemical perturbations.64,65 Therefore, when conceiving ROS-based nanomedicines, we are obliged to consider the systematic nanobio interactions for the optimization of therapeutic outcomes. For example, a theoretical study has been undertaken to reveal how the size of TiO2 nanoparticles in

sunscreens can affect the efficacy, aesthetics, and ROS-related toxicity (Figure 6).66 It seeks to deliver an optimal performance quantitatively in terms of the above three parameters, which inspires researchers to conduct more extensive evaluations on the as-prepared ROS-related nanomedicine, not just on their therapeutic efficacy. I


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dynamically changing biological environment? Why are some of the ROS-related therapeutic modalities counterproductive to reach their therapeutic expectations? Can we guarantee the bioavailability, biodegradability, and biocompatibility of asprepared nanomedicines after administration? These scientific issues are driving researchers to perform more detailed while comprehensive investigations on these nanomedicines, thus benefiting future advances in biomedical applications.

The above discussions on nanobio interactions are based on their physiological effect. In the pathological region, the unique nanobio interactions may also significantly enhance the therapeutic outcomes of ROS-based nanomedicines. For example, researchers indicated that normalization of tumor blood vessels with large heterogeneous pores would favor the delivery of nanomedicines in a size-dependent manner [i.e., enhanced permeability and retention (EPR) effect].67 Using a mathematical model, they further confirmed that steric and hydrodynamic hindrances make the large nanoparticles more difficult to enter tumors. Therefore, for cancer therapeutics, the first criterion in the design of ROS-based nanomedicines is small-enough volume for favoring their transport within the vascular system, accumulation into tumor issue, and excretion out of the body.68−70 ROS nanotechnology integrates the chemical and biological principles at nano levels, for the construction of nanomedicines with enhanced ROS-regulating efficiency and improved therapeutic outcomes. As an emerging subdiscipline, ROS nanotechnology provides feasible redox-regulation strategies for disease treatment, pushing forward the further advances of therapeutic modalities.

1.3. Scope of This Review

ROS science progresses fast. However, no effort has been made on a comprehensive overview of this highly attractive and important research field. Considering that significant progresses have been made in the past two decades, and current research in this field, especially in ROS-based nanomedicine, is still under intensive investigation, in this review, we will, for the first time, discuss the fundamental chemical principles of various ROS-based therapeutic platforms systematically and comprehensively. First, the unique material chemistry of ROS-based nanomedicines will be discussed to elucidate the ROS-regulating mechanisms of several representative nanomaterials. Second, recent progresses on ROS-based cancer nanotherapies will be summarized in detail, ranging from PDT, SDT, RT, CDT, and CDR, to synergistic cancer therapy. Third, recent advances in ROS-related nanotherapy for other pathological abnormalities, such as brain diseases, inflammatory disease, cardiovascular disease, and bacterial infection, will also be included in this review. Finally, key scientific issues encountered in the evolution of ROS science will be discussed in depth, and perspectives indicating future directions of ROS-based nanomedicines will also be provided. It is highly expected that the clearer elucidation of this field will help us to unlock the innate powers of ROS for contributing to the health of human beings.

1.2. Status Quo of ROS Science in Nanomedicine

Just as Whitesides’s statement on the 150th anniversary of BASF, “the end of one era and the beginning of another”,71 ROS science also enters into a new era during a century’s leapforward development (Figure 7), shifting from initial discrete researches on ROS-related fundamental chemical mechanisms and biological principles (i.e., ROS chemistry and biology), to the subsequent systematic scientific endeavors investigating the chemical and biological characteristics of ROS-related nanomaterials for rational therapeutic approaches (ROS nanotechnology). The development of ROS science can be divided into two stages: (1) The first stage is from the 1890s to the 1990s. During one century’s investigation and exploration, researchers have gradually uncovered the veil of ROS based on the related chemical and biological phenomena.72−77 Moreover, ROSrelated therapeutic modalities, such as PDT and sonodynamic therapy (SDT), have been developed preliminarily.78−81 (2) The second stage is in the last 20 years. The emergence of redox-active nanomaterials has provided advanced ROSregulating approaches for favoring numerous therapeutic applications, thus contributing to the second development of ROS science. This stage stems from the advent of nanozymes, when specific nanomaterials with intrinsic enzyme-mimicking catalytic performance, such as CeO2 and Fe3O4 nanoparticles, were applied for biosensing or therapeutic applications.82−85 Along with the development of nanosynthetic chemistry, numerous ROS-based nanoplatforms have been fabricated subsequently to guide ROS generation, depletion, and transition in vivo.86−88 For example, in cancer therapeutics, these nanomedicines have greatly augmented the outcomes of related therapeutic modalities, such as PDT,89−91 SDT,92−94 radiotherapy (RT),95 chemodynamic therapy (CDT),62 controlled drug release (CDR),96,97 and synergistic cancer therapy.98 However, although considerable achievements have been made in ROS-based nanomedicine, our current understanding on the relationships between their therapeutic functions and the underlying chemistry/biology remains preliminary. How do these nanomedicines guide the evolution of ROS in the

2. MATERIAL CHEMISTRY OF ROS-BASED NANOPLATFORMS The material chemistry of ROS-based nanomedicines determines their in vivo chemical characteristics and biological behaviors. In this section, we will highlight the representative redox-active materials, such as photosensitizers (PSs),99 sonosensitizers,100 and nanozymes,101 with a concise elucidation on their unique chemistries that actuate in vivo ROS generation/depletion for therapeutic intervention. Moreover, to investigate the ROS-regulating efficacies of these emerging therapeutic platforms, current analytical techniques for ROS evaluation have also been discussed in this section, for helping readers gain a better understanding of the material (nanomedicine)−chemistry (ROS) interactions. 2.1. ROS-Generating Nanoplatforms

The generation of excessive ROS in pathological sites has been employed as a general therapeutic approach for numbers of pathological abnormalities, such as cancer56 and bacterial infection.102 This strategy stimulates the emergence of numerous ROS-generating platforms to upregulate the intracellular redox status under the assistance of exogenous/ endogenous interventions, such as light, ultrasound (US), and chemical species. For example, PSs-loaded nanosystems, such as protoporphyrin (PpIX),103−105 ZnPc,106 or TiO2107-loaded nanoplatforms can respond to exogenous light irradiations to enable remote-controlled photocatalytic ROS generation for PDT; sonosensitizers-delivered nanosystems, such as PpIX,108 rose bengal,109,110 TiO2,111,112 or black phosphorus (BP)113J


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Figure 8. Intrinsic peroxidase-like activity of Fe3O4 nanoparticles for •OH production. (a) Transmission electron microscopy (TEM) images of Fe3O4 nanoparticles. Scale bar, 50 nm. The peroxidase-like activity and •OH-generating performance of Fe3O4 nanoparticles are affected by pH (b) and H2O2 concentration (c). MNP, magnetic nanoparticle; HRP, horseradish peroxidase. Reprinted with permission from ref 85. Copyright 2007 Nature Publishing Group.

Figure 9. ROS-scavenging nanoplatforms. (a) CeO2 nanoparticles as SOD and CAT mimics for ROS scavenging. Reprinted with permission from ref 131. Copyright 2015 John Wiley and Sons. (b) PB nanoparticles with efficient ROS-scavenging capability via multienzyme-like activity including peroxidase, CAT, and SOD. Reprinted with permission from ref 143. Copyright 2016 American Chemical Society.

activities of fullerene derivatives has been considered as the milestone in the development of nanozyme.82,122,123 A mechanistic study in 2004 proposed that electron-deficient regions on the C60 sphere could work in concert with malonyl groups to electrostatically stabilize O2•−, thus promoting its dismutation.124 The unique ROS-detoxifying capabilities of fullerene derivatives have been extensively applied for various antioxidative applications, such as neuroprotection and antiaging.122 The next wave of ROS-scavenging nanozymes is the exploration of CeO2, which has become the most prevalent inorganic nanomedicine for current antioxidative treatment (Figure 9a).125−131 Due to the mixed valence states of cerium (Ce3+ and Ce4+) and the presence of compensating oxygen vacancies,132−135 they are chemically active and can scavenge O2•− and H2O2 efficiently by reversibly binding oxygen atoms and shifting between Ce3+ (reduced) and Ce4+ (oxidized) forms,136−138 presenting SOD- and CAT-mimetic activities, which underpins their vital role in numerous antioxidative therapeutics, such as radiation protection139,140 and retinal degeneration prevention.141,142 Other inorganic nanomaterials such as Prussian blue (PB) (Figure 9b),143 Pt,144 and NiO145 have also been evidenced with ROS-scavenging activities, benefiting the design of next-generation ROS-scavenging nanomedicines by taking advantage of their intrinsic catalytic properties.

deliveried nanoplatforms can be activated by US to enable efficient sonocatalytic ROS generation for SDT; a number of inorganic nanozymes with peroxidase-like activities, such as Fe3O4 nanoparticles (Figure 8),85 FeS nanoparticles,114,115 CuS nanoparticles116,117 and V2O5 nanowires,118 can convert endogenous biological H2O2 into highly cytotoxic •OH for CDT or antibacterial treatment. These chemical reactions are accompanied by the transition of energy. PSs, sonosensitizers, and nanozymes are capable of extracting exogenous optical, mechanical, and chemical energy, respectively, and transfer them into the internal chemical energy of ROS based on their unique physicochemical properties. The large family of ROS-generating nanoplatforms with intrinsic chemistries plays a significant role in the development of redox-upregulating-related therapeutic applications, such as antineoplastic therapy and antibacterial therapy. In the following sections, we will present systematic elucidations on the interdependent relationships between these designed ROS-generating nanosystems and their underlying therapeutic mechanisms. 2.2. ROS-Scavenging Nanoplatforms

The development of enzymology has favored the generation of a variety of ROS-scavenging materials with enzyme-mimicking functions, such as SOD/CAT-like activities, to downregulate aberrant ROS status to levels that are compatible with cellular biological functions.119−121 The discovery of SOD-mimicking K


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Figure 10. Current analytical techniques available for the measurement of ROS produced/depleted by nanomaterials. (a) Chemical structures of the spin trapping reagents (a1) and their reactions with ROS to generate radical adducts for detection (a2). EMPO, 5-(ethoxycarbonyl)-5-methyl-1pyrroline N-oxide; DEPMPO, 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide; CYPMPO, 5-(2,2-dimethyl-1,3-propoxycyclophosphoryl)-5methyl-1-pyrroline N-oxide. Reprinted with permission from ref 146. Copyright 2013 Elsevier Ltd. (b) Biochemical assays. (b1) Chemical mechanism for SOSG-based 1O2 detection. Reprinted with permission from ref 157. Copyright 2011, John Wiley and Sons. (b2) TMB coloration. Reprinted with permission from ref 17. Copyright 2017 Nature Publishing Group. (b3) MB decolorization assay. Reprinted with permission from ref 158. Copyright 2017 Elsevier Ltd.

determination of ROS.17,158 To further investigate the cellular concentration/distribution of ROS, a fluorescent probe such as 2′,7′-dichlorofluorescein diacetate (DCFH-DA) has also been applied, which can transform into 2′,7′-dichlorofluorescein (DCF) after interacting with cellular ROS for detection. It is noted that, although these biochemical assays provide useful tools for visualizing the quantitative changes of ROS, however, they suffer from nonspecificity and may be intervened by other types of ROS in the reaction systems.

2.3. Related Analytical Techniques

Accurate characterizations of ROS produced or scavenged by these redox-active nanomaterials are beneficial for evaluating their in vivo therapeutic performances. Among various developed ROS-detecting techniques, electron spin resonance (ESR) spectroscopy is the most prominent one, which is based on the absorption of electromagnetic radiation by a paramagnetic sample in a magnetic field.146−148 To assist ROS detection, a spin trapping method was also developed.149 These as-added trapping agents, such as 5,5-dimethyl-1-pyrroline-Noxide (DMPO), 5-tert-butoxycarbonyl-5-methyl-1-pyrroline Noxide (BMPO), and 2-methyl-2-nitrosopropane (MNP), can react with ROS and give rise to radical adducts that can be subsequently identified (Figure 10a).150,151 For current researches focusing on ROS-related nanotherapeutics, ESR measurement and spin trapping strategies are indispensable for the detections of cytotoxic 1O2 and •OH generated by prepared nanomedicines. However, due to the short lifetimes of radical adducts, ESR spectroscopy may not be competent enough to reflect the realtime quantitative dynamics of ROS.152,153 Biochemical assays, such as fluorescent, luminescent, and colorimetric probes, have been extensively developed for the kinetic evaluation of ROSinvolved reactions (Figure 10b).154,155 For example, singlet oxygen sensor green (SOSG) has been explored as a feasible fluorescent sensor for 1O2 detection;156,157 3,3′,5,5′-tetramethyl-benzidine (TMB) coloration assays and methylene blue (MB) decolorization assays are also applicable for colorimetric

3. ROS-BASED CANCER NANOTHERAPY The elevated ROS level is the hallmark of cancer cells that correlates with the aggressiveness of neoplasms (Figure 11). However, this phenomenon leads to a biological discrepancy between the factual carcinogenic potential of ROS and our general notion that an excessive amount of ROS may lead to random oxidative damage of cells. Why can cancer cells maintain high ROS levels while retaining their high reproductive capacity for carcinogenesis? In cancer cells, the increment of ROS can activate equally potent, endogenous cellular antioxidant defense mechanisms, leading to the upregulation of antioxidants and the shift of redox dynamics from the regular redox homeostasis to a new steady equilibrium state with both high ROS generation and elimination rates, thus maintaining the total ROS levels below the toxic threshold.10 These endogenous redox-adaptive mechanisms, such as activation of redox-sensitive transcription factors (e.g., κB and Nrf2), expression of ROS-scavenging L


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each cancer therapeutic modality by concentrating on the representative ROS-based nanoplatforms, and finally we present the recent advances in the promotion of these cancer therapeutics. 3.1. Photodynamic Therapy (PDT)

PDT is the first redox-regulating therapeutic modality developed in ROS science, which can date back to the Raab’s demonstration on light-triggered cytotoxicity in 1900.78 As a typical noninvasive therapeutic modality, PDT has been approved in the clinic for the treatment of lung cancer, skin cancer, esophageal cancer, etc.159 It consists of three basic components: PS, light, and tissue oxygen. The exogenous visible light activates nontoxic PS to transfer its excited-state energy to ambient oxygen for ROS generation, which can lead to the apoptosis and/or necrosis of malignant cells, as well as the stimulation of the host immune system (Figure 12).160,161 Figure 11. ROS regulation and tumorigenesis at different stages. Cells undergo a progressive increase in ROS levels during the transformation from normal status to invasive carcinomatous condition (solid arrows). However, these cancer cells can escape oxidative damage by reinforcing their intrinsic antioxidant defenses that will lower ROS levels (dashed arrows). Therefore, it is here proposed that we could force the accumulation of excessive ROS in tumor that overwhelms the antioxidant systems to induce cell death for anticancer therapy (solid red arrows). Reprinted with permission from ref 56. Copyright 2013 Nature Publishing Group.

molecules (e.g., SOD and GSH), or alterations of genes via varied mechanisms (e.g., genetic or epigenetic pathways), can counteract the potential toxic effects of excessive ROS, thus allowing cancer cells to escape oxidative damage and survive under high redox stress.10 As a consequence, cancer cells would be more dependent on the endogenous antioxidant system to maintain the newly formed redox homeostasis and more vulnerable to further intensified oxidative stress by exogenous ROS-generating agents. Thus, the abrogation of this adapted endogenous redox equilibrium state, if possible, by exogenous interventions, for example, ROS-generating nanomaterials, which result in much elevated ROS levels beyond the cellular tolerability threshold as antioxidant systems become overwhelmed, could be an attractive but feasible strategy to preferentially devastate cancer cells and may therefore have significant therapeutic implications. This strategy, which is based on the cancer redox biology, provides a material-guided, ROS-mediated therapeutic approach to disrupt the self-adaptation mechanisms of cancer cells and thus exert a therapeutic effect. In the consideration of the maneuverability of the nanomedicine-involved therapeutic process, this strategy can be highly competent for antineoplastic therapy. On the other hand, the intrinsic redox-elevating feature of cancer cells also leads us to consider another feasible, or complementary approach for cancer treatment. These excessive ROS in cancer cells can act as “biochemical engine” to activate ROS-responsive nanomedicines for on-demand drug release. Therefore, adding to the aforementioned strategy, ROSresponsive performances of materials can also be taken into consideration for improving therapeutic effects. Stepping from ROS biology to ROS pathology and to ROS oncology, the development of ROS-relevant researches has favored the emergence of several redox-related therapeutic modalities, such as PDT, SDT, RT, CDT, and CDR. In this section, we will demonstrate the physicochemical principles of

Figure 12. Biochemical mechanisms of PDT. The excitation of PSs leads to the overproduction of intracellular ROS that initiate the apoptosis or necrosis of cancer cells, accompanied by the activation of biological cascades such as the secretion of proinflammatory cytokines and the recruitment of immunocytes. Reprinted with permission from ref 161. Copyright 2011 American Cancer Society.

Based on the reaction mechanisms, PDT can be further categorized into two subtypes: type I and type II. Under light irradiation, PSs transform from their ground singlet state to the excited triplet state and then participate in two reaction pathways:162 in type I PDT, PSs react with biological substrate to generate radical intermediates, which can react with ambient triplet oxygen (3O2) and H2O to generate O2•− and •OH subsequently; in the type II PDT, PSs can transfer their energy to surrounding 3O2 directly for the generation of cytotoxic 1O2. Therefore, type I PDT could be an oxygen-independent process, while type II PDT can take place only in welloxygenated environments. 3.1.1. Nanomedicine-Facilitated Photoactivation. Generally, an ideal PS in PDT is supposed to be characterized by high quantum yield, maximum light absorption, and negligible dark toxicity.162 Based on their composition, PSs can be classified as organic and inorganic ones. The past several decades have witnessed the three-stage developments of organic PSs, from the first-generation PSs (porphyrin derivatives) with primitive photosensitizing property, to the second-generation PSs [e.g., chlorin e6 (Ce6), phthalocyanines, M


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Figure 13. Inorganic PSs. (a) Graphene quantum dots with a high quantum yield and broad absorption band for 1O2 generation. (a1) TEM image of graphene quantum dots. Scale bar, 20 nm. (a2) 1O2 generation mechanisms by traditional PSs (left) and graphene quantum dots (right). Reprinted with permission from ref 174. Copyright 2014 Nature Publishing Group. (b) BP nanosheets as effective and biodegradable PSs for 1O2 generation. (b1) TEM image of as-prepared BP nanosheets. (b2) Time-dependent UV−vis absorption spectra of 1,3-diphenylisobenzofuran (DPBF) in the presence of BP nanosheets. (b3) Schematic illustration of photocatalytic 1O2 generation by BP nanosheets. Reprinted with permission from ref 178. Copyright 2015 American Chemical Society.

quantum dots show higher 1O2 quantum yield than conventional PSs due to their unique band structures (Figure 13a);174 BP nanosheets exhibit excellent biodegradable properties, thus solving the low biodegradability issue of most inorganic PSs (Figure 13b).178

etc.] with improved tumor selectivity, and to the thirdgeneration PSs (nanocarriers-augmented composite PSs) with improved tumor accumulation.163−165 However, most organic PSs still suffer from photoinduced or enzymatic degradation, making them counterproductive for achieving the expected therapeutic outcomes. Comparatively, inorganic nanomaterials with intrinsic chemical stability, have attracted extensive attention recently for fabricating next-generation PSs. The photosensitivities of inorganic semiconducting nanomaterials are based on their unique energy band structures, which confer them with lighttriggered ROS-generating capabilities for subsequent therapeutic applications. However, unlike most organic PSs involved in type II PDT, many inorganic PSs can participate in type I PDT processes.162 The application of inorganic nanomaterials in PDT can be traced back to 2009, when Rozhkova et al. first reported that TiO2 nanoparticles could initiate programmed glioblastoma cell death as a consequence of phototoxicity.166 Mechanistic studies further revealed that, under UV light irradiation, electrons in the valence band of TiO2 can be excited and then shift to the conduction band, resulting in the formation of electron−hole pairs, which can further interact with surrounding O2 and H2O to generate ROS.167 Such a discovery has also facilitated the application of other inorganic semiconducting nanomaterials in PDT, such as Si nanoparticles,168,169 SnWO4 nanoparticles,170,171 CdSe quantum dots,172,173 graphene quantum dots,174−177 BP nanosheets,178 bismuth oxyhalide nanosheets, 179 etc. These emerging inorganic PSs with different physicochemical features display varied characteristics in PDT. For example, β-SnWO4 nanoparticles can present acute phototoxicity under blue-light LED illumination rather than UV irradiation;170 graphene

3.1.2. Deep PDT by Different Excitation Sources

In conventional PDT, PSs are usually excited by shortwavelength UV−vis light (spectral range in 400−700 nm), which features poor tissue penetration.162 Fortunately, nanotechnology has provided feasible strategies to overcome such a limitation, facilitating the development of “deep PDT”. Based on the unique physicochemical properties of some inorganic materials, such as photoconverting nanoparticles that can convert exogenous near-infrared light (NIR) or X-ray into UV− vis light, or self-illuminating materials that can emit endogenous light within tumor tissues, PSs can be indirectly activated via Förster (fluorescence) resonance energy transfer (FRET) from these functional inorganic materials to PSs for initiating ROS generation within deep-seated tumors. NIR light (spectral range in 700−1100 nm) lies in the “optical transparency window” of biological tissues, which promises deeper tissue penetration and less energy attenuation than visible light. Typically, NIR-trigged deep PDT is based on upconversion nanoparticles (UCNPs) to convert NIR into UV−vis light, and thus to activate as-coupled organic/inorganic PSs via FRET. Year 2012 marked the development of UCNPbased composite nanosystems for deep PDT when Idris et al. first fabricated silica-coated UCNPs coloaded with ZnPc and MC540 as remote-controlled, NIR-excited PDT platforms.106 Inspired by this pioneering work, we have constructed silicacoated UCNPs codelivered with photosensitive silicon phthalocyanine dihydroxide (SPCD) and bioreductive proN


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PDT.184 The ever-increasing number of literatures in this field have further evidenced the effectiveness of such an advanced optical technology in PDT.185,186 Besides NIR light, X-ray is also an important physical excitation source for deep PDT. The photon energy of clinical X-ray is in the range of several kiloelectronvolt (keV) to several megaelectronvolt (MeV), making it free from the tissue penetration limitation.187−190 However, X-ray cannot effectively activate most traditional organic/inorganic PSs because of the apparent energy mismatch between the photon energy of X-ray (keV-MeV) and the singlet−triplet energy gap of PS (1−3 eV).162 Fortunately, some nanomaterials with unique optical properties have been fabricated to harvest X-ray to indirectly excite PSs, such as scintillating nanoparticles (SCNPs) and persistent luminescence nanoparticles (PLNPs). SCNPs can serve as energy mediators to convert X-ray radiation into UV−vis light through a typical scintillation process.191 Under X-ray radiation, electron−hole pairs are generated, and the energy can be transferred to the luminescent ions of SCNPs. After these excited ions return to their ground state, the UV−vis luminescence is emitted, which can be utilized for PS excitation. A representative study by Chen et al. presented a composite nanosystem for SCNP-mediated deep PDT, by coating highly hydrolytic SrAl2O4:Eu2+ (denoted as SAO) nanoparticles with silica layers followed by MC540 loading (Figure 15a).192 The inner SAO core is capable of converting X-ray photons to visible photons, and thus activates as-delivered MC540 to initiate 1O2 generation. In an alternative work, Tang et al. fabricated mesoporous LaF3:Tb SCNPs as Xray energy transducers and PS carriers for deep PDT.193 Moreover, Lan et al. also fabricated 2D metal−organic layers (MOLs) as an X-ray scintillator for enhanced PDT with deepened tissue penetration.194 Heavy Hf atoms in the [Hf6O4(OH)4(HCO2)6] secondary building units (SBUs) can efficiently absorb X-rays and transfer optical energy to integrated Ir[bpy(ppy)2]+ or [Ru(bpy)3]2+ moieties for favoring ROS generation. Moreover, the 2D structure of MOLs allows these ROS to diffuse freely,195 further improving PDT outcome. PLNPs are also promising light conversion agents to be applied in X-ray-activated PDT, which can store energy during excitation and then slowly emit afterglow phosphorescence.162 Importantly, they can act as the second light source in tumor to continue exciting the coupled PS after the removal of X-ray irradiation, and thus to overcome the depth barrier of tissue penetration. Ma et al. first reported X-ray excited ZnS:Cu,Co afterglow nanoparticles for PDT in 2014.196 Song et al. also fabricated W(VI)-doped PLNPs for deep and repeatable PDT under the activation of low-dose X-ray (Figure 15b).197 In addition, Fan et al. also reported the construction of injectable and periodically rechargeable persistent luminescence implants by dissolving ZnGa1.996O4:Cr0.004 PLNPs in poly(lactic-coglycolic acid) (PLGA)/N-methylpyrrolidone (NMP) oleosol for localized cancer therapy,198 which presented prolonged luminescence lifetime for improved PDT outcome. However, energy attenuation is inevitable when NIR or X-ray permeate through normal tissues, which results in lowered ROS-generating efficiency. Self-luminating materials, which can emit light without the assistance of exogenous irradiations, have also been developed for PS activation within tumors, thus to completely break the depth dependency of PDT. For instance, radionuclides, such as radiolabeled 2′-deoxy-2′-(18F)fluoro-Dglucose (FDG), can serve as an ideal intratumoral light source

drug tirapazamine (TPZ) for simultaneous NIR-activated deep PDT and hypoxia-specific chemotherapy.180 Given that these as-delivered organic PSs are not stable enough in biological environment, a number of inorganic PSs have also been integrated with UCNPs to construct composite nanoplatforms for NIR-mediated deep PDT.181 For example, Lin et al. have first constructed UCNP@TiO2 composite nanosystems in 2015 (Figure 14).182 In this work, TiO2

Figure 14. Proposed working mechanism of UCNPs@TiO2 nanocomposites. ET, energy transfer; CB, conduction band; VB, valence band. Reprinted with permission from ref 182. Copyright 2015 American Chemical Society.

nanoparticles were directly decorated on the surface of UCNPs and then irradiated by 980 nm laser. It has been further evidenced that this NIR-mediated PDT process could induce cancer cell death via a mitochondria-involved apoptosis pathway. The expression of caspase 3 in tumor tissue would be upregulated following PDT, leading to the apoptosis of cancer cells, and thus presenting a complementary therapeutic effect. In an alternative work, a TiO2 layer was created on the surface of mesoporous silica-coated UCNPs for higher PS loading efficiency.183 Importantly, it is further demonstrated that the application of 808 nm laser in PDT can mitigate the photodamage of tissues irradiated by a 980 nm laser, which is instructive for future PS design. The aforementioned therapeutic paradigms are based on the NIR one-photon excitation. As a typical nonlinear optical phenomenon, NIR two-photon excitation, which is initiated by short-pulsed (∼100 fs) lasers, has also been developed to directly activate PSs with two-photon absorption (TPA) for deep PDT. It offers precise 3D manipulation of therapeutic regions, featuring enhanced spatial selectivity compared with conventional NIR one-photon excitation.162 In the past few years, numerous TPA PSs have been explored to improve the therapeutic efficacies of PDT. For example, fluorogens with aggregation-induced emission (AIE) characteristics have been designed to serve as effective TPA PSs for efficient and precise O


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Figure 15. X-ray-activated photosensitizing nanoplatforms. (a) Scintillator-based nanoplatforms. (a1) Working mechanism of SAO@SiO2 nanoparticles. XEOL, X-ray excited optical luminescence. (a2) TEM image of bare SAO nanoscintillator. (a3) TEM image of as-prepared SAO@ SiO2 nanoparticles. The silica coating consists of inner solid layer and outer mesoporous layer as circled in the image. (a4) Time-dependent biodegradation process of SAO@SiO2 nanoparticles evaluated in simulated body fluid. Scale bars, 100 nm. Reprinted with permission from ref 192. Copyright 2015 American Chemical Society. (b) W(VI)-doped persistent luminescence nanoparticles (PLNPs) for depth-independent and repeatable PDT. (b1) Synthetic procedure and therapeutic principles of X-ray activated PLNPs. (b2) Proposed persistent luminescence mechanism of as-designed nanoplatform. The corresponding physical processes, such as electronic transitions, electron transfer, as well as trapping and detrapping of electrons, are also displayed in the figure. Reprinted with permission from ref 197. Copyright 2018 John Wiley and Sons.

for Cerenkov radiation (CR)-mediated deep PDT because of their high positron (β+) emission decay.199,200 A prominent work by Kotagiri et al. presented that the simultaneous administration of TiO2-Tf nanoparticles and radionuclide 64 Cu (a β particle emitter) in tumor-bearing mice would lead to the complete tumor regression (Figure 16).201 Such a therapeutic effect is based on CR generated by radionuclide 64 Cu, which can activate coupled TiO2 nanoparticles to facilitate electron−hole pair formation for ROS generation. This work offers a new way to harness self-luminating radionuclides and low-radiance-sensitive TiO2 photocatalysts to achieve depth-independent deep PDT, benefiting future works to improve the therapeutic efficiency of cancer. 3.1.3. Recent Advanced Strategies to Augment PDT. Although considerable achievements have been made in this field of PDT, however, their therapeutic efficacies are still not satisfactory enough to fully meet the ever-stringent requirements of clinical translation. Recent advances in ROS science and material chemistry have provided new design rationales of ROS-based nanoplatforms for improved PDT efficacy, which can be categorized into the following three methodologies: (1) ROS amplification: investigating the interactions between materials and chemical species (such as ROS) to further elevate ROS-generating performance; (2) Tumor microenvironment (TME) response: exploring the interactions between materials and the biological stimuli in TME to further

regulate biological behaviors of nanomedicines; (3) TME modulation: evaluating the interactions between materials and the intrinsic features of TME to modulate TME and favor PDT process. A typical work by Durantini et al. first presented an “autocatalytic strategy” to improve PDT, by ROS-mediated second PS activation for ROS amplification (Figure 17).202 The as-designed PS is based on a two-segment PS-trap molecule where juxtaposed antioxidant (trap segment, chromanol) and prooxidant (PS segment, Br-BODIPY) are integrated together. Oxidation of the trap segment by generated 1O2 results in the restored sensitizing properties of the PS segment, leading to 40fold enhancement in 1O2 production. This pioneering work is instructive for the design of efficient ROS-based nanomedicines by utilizing juxtaposed antioxidant-pro-oxidant antagonistic chemistry. In addition to the ROS-generating performance, tumorspecific localization of nanomedicine is also of great significance to guarantee their bioavailability and subsequent PDT outcome. In a recent work, Ai et al. presented a unique TME-responsive strategy for endogenous enzyme-triggered covalent crosslinking of peptide-premodified UCNPs (CRUN) in the tumor region, thus to facilitate tumor accumulation and augment PDT efficiency (Figure 18).203 Intratumoral cathepsin B (CtsB) catalyzes the peptide cleavage to induce the crosslinking between the exposed groups on neighboring particles, P


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Figure 16. Cerenkov radiation (CR)-excited nanoplatforms. (a) Synthetic procedure of TiO2-titanocene (Tf)-transferrin (Tc). (b) TEM images of TiO2-polyethylene glycol (PEG), TiO2 aggregates, TiO2-Tf, and TiO2-Tf-Tc (from left to right, respectively). Scale bar, 50 nm. (c) Comparison of the cellular viabilities treated with TiO2-Tf, Tc-Tf, and TiO2-Tf-Tc with and without exposure to 64Cu and 2′-deoxy-2′-(18F)fluoro-D-glucose (FDG) on HT1080 cells. ***P < 0.001. (d) Schematic illustration for the CR-mediated excitation of TiO2 nanoparticles. Reprinted with permission from ref 201. Copyright 2015 Nature Publishing Group.

Figure 17. “Autocatalytic Strategy” by ROS-mediated activation of dormant PS for chemically controlled ROS amplification. Reprinted with permission from ref 202. Copyright 2016 American Chemical Society.

circumvents the overheating effect of 980 nm laser irradiation that is extensively employed for UCNP excitation. To further promote the targeting abilities of nanomedicines in PDT, affinity ligands have also been decorated on these nanosystems for facilitating their cellular internalization and even subcellular

thus promoting the intratumoral UCNP accumulation by EPR effect (passive targeting).204 Compared with the pristine UCNPs, the CtsB-triggered CRUN possess an enhanced light upconverting emission when illuminated at 808 nm, which not only amplifies the 1O2 generation from attached PSs but also Q


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Figure 18. Optimization of PDT efficacy in a TME-responsive manner. Reprinted with permission from ref 203. Copyright 2016 Nature Publishing Group.

Figure 19. “O2 evolution” approach to modulate hypoxic TME for enhancing PDT. (a) MnO2-nanosheets-coated hybrid SPNs (SPN-M) for overcoming hypoxia. (a1) Working mechanisms of SPN-M. (a2) Representative TEM images of SPN-M. (a3) Relative fluorescence density of SOSG to investigate the generation of 1O2 in SPN-0 or SPN-M dispersion under hypoxic conditions. Reprinted with permission from ref 213. Copyright 2018 American Chemical Society. (b) MnFe2O4-anchored MSNs (MFMSNs) for continuous O2 evolution and hypoxia regulation. (b1) Working mechanism of MFMSNs. (b2) TEM image of as-prepared MFMSNs. Scale bar, 60 nm. (b3) H2O2 decomposition after treating with MFMSNs in phosphate buffered solution (PBS). Reprinted with permission from ref 220. Copyright 2017 American Chemical Society.

interventions may be effective to significantly improve PDT efficacy. Recent advances in nanotechnology have promoted the emergence of numerous nanosystems with TME-responsiveness and O2 generation capabilities for modulating hypoxia and enhancing PDT.210 These exquisite nanoplatforms were established by integrating organic enzymes or inorganic nanozymes, such as CAT,211,212 MnO2,213−218 or other catalytic nanomaterials219−222 that can convert intratumoral H2O2 to O2. For example, Zhu et al. first developed MnO2-nanosheetscoated semiconducting polymer nanoparticles (SPNs) that can initiate O2 generation in hypoxic tumor for promoting a PDT process (Figure 19a).213 The SPN core can respond to NIR irradiation and generate ROS subsequently, while the asdecorated MnO2 nanosheets act as a sacrificing component to convert intratumoral H2O2 to O2 under acidic TME, thus upregulating the oxygen level and augmenting the PDT effect. In another representative work, Hyeon and his co-workers also fabricated continuous O2-generating MnFe2O4-anchored MSNs for enhancing PDT (Figure 19b).220 The outer MnFe2O4 nanoparticles can catalyze H2O2 into O2 in hypoxic tumor,

positioning (active targeting). We have constructed a transcriptional activator protein (TAT) and three-amino acid peptide arginine-glycine-aspartic acid (RGD) coconjugated mesoporous silica nanoparticles (MSNs) as Ce6 carriers to favor sequential targeting for intranuclear photosensitization.205 RGD peptides endow the nanosystem with affinity to tumor vasculature and tumor cell membranes,206 while TAT peptides further favor the cell nucleus penetration of MSNs,207−209 thus enabling the efficient intranuclear accumulation of Ce6, significantly improving the therapeutic efficacy of PDT. For PDT nanoplatforms, their ROS-generating capabilities are closely related to the oxygen content of TME. However, hypoxia exists in most tumors (pO2 < 2.5 mmHg),33 which compromises the therapeutic performances of PDT. It is known that hypoxia results from oxygen diffusion limitation in primary tumors (diffusion-limited hypoxia) or temporally unstable blood flow in tumor microvascular networks (fluctuating perfusion-limited hypoxia),33 representing a key microenvironmental factor governing the outcome of PDT. Therefore, reoxygenation in TME by endogenous or exogenous R


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Table 1. Summary of the Strategies for the Fabrication of New Photodynamic ROS-Generating Platforms strategies Creation of new PSs with unique physicochemical properties

Utilization of different lights to favor tissue penetration

Design of new platforms based on the features of TME

materials Organic dyes: molecular derivatives of conventional PSs, nanoparticulate organic dyes Inorganic semiconductors: TiO2, β-SnWO4, graphene quantum dots, BP, bismuth oxyhalide, CdSe NIR-activated materials: UCNP-based nanoplatforms, TPA X-ray-activated materials: SCNPs, PLNPs CR-activated materials: TiO2, Ce6 TME-responsive nanomaterials: biochemical-triggered PDT enhancement TME-modulating nanomaterials: reoxygenation in hypoxic tumors

working mechanisms Intramolecular or intermolecular resonance energy transfer Separation of electrons and holes from the covalent band and conduction band FRET from photoconverting or selfilluminating nanoparticles to PSs

Mutual interactions between nanomedicines and TME to favor tumor targeting Decomposition of hyperoxide or water to generate O2 and relieve hypoxia

favoring the subsequent ROS generation from activated Ce6 in MSNs. Moreover, MnFe2O4 nanoparticles are not consumed during the reaction, which enables continuous O2 generation. However, the aforementioned reoxygenation strategy may encounter difficulties due to the limited cellular H 2 O 2 concentration.223 Researchers are now seeking to conceive other applicable approaches to modulate hypoxia by means of, for example, selecting H2O as an alternative O2-generating reactant because H2O is the most abundant compound in living organisms. Two recent reports by Zhang and his co-workers have elucidated different H2O-involved, O2 evolution strategies. They first fabricated carbon-dots-decorated C3N4 for lighttriggered in vivo water splitting and O2 generation to support photodynamic ROS generation.224 Then, they also encapsulated CaO2 and MB into liposome to construct an O2 selfsufficient nanoplatform, in which CaO2 and H2O acted as the O2-generating source and biological trigger, respectively.225 These two approaches are effective for intratumoral reoxygenation in a H2O2-independent manner. As one of the most pivotal cancer therapeutic modalities, PDT develops fast armed with the advances in nanoplatform fabrication strategies (Table 1). It is expected that the achievements in nanotechnology will further boost the development of PDT in the next several decades.

characteristics

refs

High biocompatibility, mainly involved in type II PDT, low stability High stability, tunable optical properties, involved in type I and type II PDT. Deep tissue penetration, potential photothermal effect Deep tissue penetration, potential radiation damage Depth-independent, low intensity High selectivity, specificity, efficiency, and bioavailability Diminished oxygen dependence and enhanced ROS-generating efficiency

163−165, 202

107, 166, 168−170, 172, 174, 175, 178, 179 106, 180−184, 186 190, 192−194, 196, 197 200, 201 203, 205

211−213, 215, 216, 219, 220, 224, 225

Figure 20. Mechanisms of US-triggered cavitation effects and their corresponding therapeutic potential. (a) Acoustic streaming (stable cavitation). (b) Sonochemistry (inertial cavitation). (c) Shock waves (inertial cavitation). (d) Liquid microjets (inertial cavitation). Among these US-triggered cavitation effects above, sonochemistry is the only chemical mechanism that initiates ROS generation. Reprinted with permission from ref 237. Copyright 2005 Nature Publishing Group.

cavitation).237 Particularly, inertial cavitation can create momentary temporospatial temperature gradients and initiate subsequent chemical reactions in biological medium (an effect termed sonochemistry), such as ROS production.237 However, in this process, the amount of as-generated ROS is not high enough to exert a therapeutic effect because of their limited generating rate and indiscriminate spatial distribution. Therefore, the assistance of additional sonosensitive compounds (i.e., sonosensitizers) is essential to guarantee high enough ROS-generating efficiency and specificity in tumor regions. It has been generally accepted that, the cavitation effect of US will lead to sonoluminescence or pyrolysis of sonosensitizers, thus contributing to the generation of ROS.92 Thanks to the development of nanochemistry, numerous sonosensitizer-based nanoplatforms have been developed for improving SDT. In this section, we will make a comprehensive overview on the state-of-the-art studies in this field and discuss the underlying material chemistry of ROS-based nanomedicines in augmenting SDT. 3.2.1. Organic Nanosonosensitizer-Augmented SDT. The early investigation on US-mediated antitumor effects of several organic molecules can be considered as the origin of SDT.238 Analogous to PDT, the first generation of sonosensitizer was based on porphyrins, such as hematoporphyrin (HP), hematoporphyrin monomethyl ether (HMME), PpIX, photofrin, ATX-70, and porphyrin derivatives,100,239 and their therapeutic effects have been confirmed by biologists and medical scientists. For example, Lv et al. demonstrated that the sonosensitization of PpIX suppressed the proliferation of human tongue squamous carcinoma SAS cells.240 Gao et al.

3.2. Sonodynamic Therapy (SDT)

Characterized by noninvasive, nonionizing, and tissue-penetrable nature, US has been extensively explored as external excitation source for numerous biomedical applications, such as ultrasonography, 2 2 6 , 2 2 7 high intensity-focused US (HIFU),228−230 low intensity-focused US (LIFU),231−233 SDT,92 and US-triggered drug release.234−236 As an emerging cancer therapeutic modality, SDT utilizes US to activate certain compounds (sonosensitizers) for initiating ROS generation in cancer cells, thus facilitating tumor eradication. Compared with light, the enhanced tissue-penetrability of US enables SDT to overcome the depth limitation, and thus exhibits greater application potential in cancer treatment. The mechanism of SDT lies in the physical interaction of US with tissues for consequent chemical cascades. Biological medium exposed to US experiences periodic pressure oscillations, resulting in the localized temperature elevation, as well as the nucleation, growth, and oscillation of gaseous cavities, a phenomenon referred to as cavitation (Figure 20). Such an effect involves rapid collapse of bubbles (inertial cavitation) and sustained oscillatory motion of bubbles (stable S


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Figure 21. Metalloporphyrin-encapsulated mesoporous organosilica nanoparticles (MONs) for efficient SDT. (a) Synthetic procedures of asdesigned nanocomposites. TEOS, tetraethyl orthosilicate. (b) Schemes of pore engineering illustrating the covalent grafting of MnPpIX into the mesopores of hollow MONs (HMONs). (c) Therapeutic mechanism of HMONs-MnPpIX-PEG. Reprinted with permission from ref 246. Copyright 2017 American Chemical Society.

may encounter enzymatic degradation in biosystems, making them counterproductive to achieve expected therapeutic outcomes. Benefiting from recent advances in nanochemistry, a number of nanocarriers have been fabricated to deliver sonosensitizers to tumor regions for improved physiological stability and enhanced tumor accumulation.245 We recently reported a biodegradable nanosystem for SDT by covalently anchoring PpIX into mesoporous organosilica nanoparticles (MONs, Figure 21).246 The large surface area and pore volume of hollow MON (HMON) facilitate PpIX loading and further Mn2+ chelating (MnPpIX).247,248 Moreover, such a nanocarrier shows improved tumor accumulation of MnPpIX by EPR effect and can degrade in the tumor region based on the redoxresponsiveness of disulfide-bond in the framework of HMONs. In an alternative work, we used HMON as a nanocarrier to

also manifested that the administration of PpIX precursor 5aminolevulinic acid followed by US treatment was capable of suppressing the expression of vascular endothelial growth factor (VEGF) in cancer cells, partially responsible for an antitumor effect. 241 It has been assumed that the US-triggered sonoluminescence might induce electronic excitation of porphyrins and subsequent chemical reactions for ROS generation.80 Based on this assumption, other nonporphyrin PSs such as rose bengal, MB, and indocyanine green (ICG) have also been demonstrated with US-triggered cytotoxic effects in early studies.80 Moreover, a number of chemotherapeutic drugs, such as doxorubicin (Dox), could also act as the sonosensitizers for SDT.242−244 However, these organic sonosensitizers suffer from low stability and low bioavailability, which hinder their further clinical applications. For example, most organic sonosensitizers T


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Figure 22. Decoration of certain molecules on the surface of TiO2 to improve their physiological stability. (a) TiO2 nanoparticles were entrapped into polyion complex micelles to enhance their dispersion stability during SDT. PIC, polyion complex. Reprinted with permission from ref 256. Copyright 2013 Royal Society of Chemistry. (b) Hydrophilized TiO2 nanoparticles (HTiO2) for SDT. (b1) Schematic for the therapeutic process, sonochemical mechanism, and related biological responses of HTiO2-based SDT. (b2) TEM images of HTiO2 nanoparticles. Scale bar, 500 nm. (b3) Time-dependent aggregation of bare TiO2 nanoparticles and HTiO2 nanoparticles, showing that HTiO2 nanoparticles keep good stability in PBS for at least 5 days. Reprinted with permission from ref 111. Copyright 2016 Nature Publishing Group.

3.2.2. Inorganic Nanosonosensitizer-Augmented SDT. The successful application of organic molecules in SDT inspires us to explore inorganic sonosensitizers for improved therapeutic efficacy. TiO2 is the first inorganic nanomaterial applied in SDT, which can generate electron−hole pairs under US treatment for ROS generation.254 However, pristine TiO2 nanoparticles suffer from low dispersion stability in biological fluids, as well as limited ROS-generating efficiency due to the fast electron−hole recombination (50 ± 30 ns).255 Therefore, they are incapable to achieve the desired treatment outcome. Based on the recent advances in surface chemistry, numbers of surface functionalization strategies have been developed to elevate the therapeutic potential of TiO2, which can be generalized as the following two methodologies: The first one is decorating certain molecules on the surface of TiO2 to improve their physiological stability. A representative work in 2013 indicated that the surface OH groups of TiO2

deliver PpIX and Dox for synergistic sonodynamic/chemotherapeutic suppression of hepatocellular carcinoma.249 It is worth noting that O2 is also necessary in the SDT process. On account of hypoxia of solid tumors that may compromise the clinical outcomes of SDT,250 the construction of composite sonosensitizers with oxygen-delivering/generating agents would be favorable to improve SDT efficacy. McEwan et al. first fabricated oxygen-loaded, lipid-stabilized microbubbles decorated with rose bengal for hypoxia modulation in the SDT process.251 In another representative work, oxygen-delivering fluorocarbon (FC) chain and sonosensitizer IR780 were chelated into the mesopores of HMONs for improving SDT outcome.252 We recently constructed a nanozyme-augmented SDT nanosystem by encapsulating MnOx and PpIX into the framework of HMONs.253 The MnOx component can convert intratumoral H2O2 into O2, favoring the subsequent UStriggered ROS-generating process. U


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Figure 23. Integration of functional materials on the surface of TiO2 for improving ROS-generating performance. (a) TiO2 nanoparticles were anchored on the surface of reduced graphene oxide (GR) nanosheets to enhance ROS-generating capability. (a1) Synthetic procedure and therapeutic applications of TiO2-based nanocomposite (denoted as MnOx/TiO2-GR). (a2) Physicochemical principles of the GR-enhanced SDT. (a3) Nyquist plots of TiO2 and MnOx/TiO2-GR obtained from electrochemical impedance spectroscopic measurements. (a4) Confocal fluorescence images of 4T1 cells after various treatments as displayed in the figure. Reprinted with permission from ref 261. Copyright 2017 American Chemical Society. (b) TiO2 nanoparticles were reduced partially to create an oxygen-deficient TiO2−x layer for SDT enhancement. (b1) Schematic illustration for black TiO2@TiO2−x (denoted as B-TiO2−x)-based nanotherapeutics. (b2) High-resolution TEM (HRTEM) image of as-synthesized B-TiO2−x. Inset is its corresponding selected area electron diffraction (SAED) pattern. (b3) X-ray diffraction patterns of TiO2 and B-TiO2−x. (b4) Quantitative analyses of C, O, and Ti elements of pristine TiO2 and B-TiO2−x based on X-ray photoelectron spectroscopy (XPS). Reprinted with permission from ref 263. Copyright 2018 American Chemical Society.

fabricated Au-TiO2 composite sonosensitizer to enhance TiO2-based SDT.255 The Au deposition prevented electron− hole recombination of TiO2 nanoparticles based on its high electroconductivity, thus favoring ROS generation.259,260 Recently, we reported on the integration of 2D reduced graphene oxide (GR) nanosheets with TiO2 nanoparticles to augment sonodynamic ROS-generating efficiency (Figure 23a).261 The 2D morphological feature of GR provides large amounts of anchoring points for TiO2, while the high electroconductivity of GR facilitates the separation of electron−hole pairs from the energy bands of TiO2, finally benefiting ROS generation.262 Moreover, the high photothermal-conversion capability of GR can also be applied for photothermal therapy (PTT) to provide a complementary therapeutic effect. In another recent work, we fabricated black TiO2@TiO2−x core/shell hierarchical nanostructure (B-TiO2−x) with abundant surface oxygen defects for simultaneous cancer SDT/PTT (Figure 23b).263 Such an oxygen-deficient layer is also capable of facilitating electron−hole separation from the covalent and conduction bands of TiO2 upon US treatment, thus benefiting ROS generation.

enable the electrostatic adsorption of graft copolymers, facilitating the formation of TiO2-entrapped micelles (Figure 22a).256 Such a core−shell architecture displayed improved dispersion stability and enhanced cellular uptake, favoring subsequent ROS generation in HeLa cells under US treatment. In another work, You et al. utilized hydrophilic carboxymethyl dextran to endow TiO2 nanoparticles with prolonged blood circulation for enhanced SDT (Figure 22b).111 In this work, researchers further manifested that the SDT process could initiate immunological cascade by facilitating the upregulation of proinflammatory cytokines and interleukins in tumor tissue. Moreover, they also demonstrated that the deeply located orthotopic tumor could be suppressed during the treatment process, further evidencing the superiority of SDT, i.e., high tissue penetrability. The second methodology is integrating functional materials on the surface of TiO2 to improve its ROS-generating performance. This strategy is inspired by recent works in catalytic chemistry, which take advantage of surface modification methods to facilitate electron−hole separation of TiO2.257,258 As a typical paradigm, Deepagan et al. first V


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Figure 24. Metal−organic-framework (MOF)-derived mesoporous carbon nanostructure (PMCS) for SDT augmentation. (a) Geometry-dependent electrostatic potential profiles for amorphous mesoporous carbon nanospheres (MCN), PMCS, and porphyrin Zn. (b) Molecular models with O−H bond length data of adsorbed H2O on the surface of PMCS and porphyrin Zn. (c) Bio-TEM images to demonstrate the cellular uptake of PMCS at low (left) and high (right) magnifications. (d) Cell viability assay of 4T1 cells after treatment with PMCS at different concentrations with/without US treatment. P > 0.05; *P < 0.05; ***P < 0.0001. Reprinted with permission from ref 275. Copyright 2018 John Wiley and Sons.

Figure 25. Endogenous catalytic generation of O2 to facilitate HIFU-triggered tumor ablation. (a) Synthetic procedures for CAT-immobilized MONs. BTES, bis[3-(triethoxysilyl)propyl]tetrasulfide; CTAC, cetyltrimethylammonium chloride; TEA, triethanolamine. (b) Multiscale hybrid nanostructure of as-prepared CAT@MONs. (c) Chemical principles of HIFU-triggered, O2-generating cancer therapy. Reprinted with permission from ref 277. Copyright 2017 American Chemical Society.

These endeavors in improving the therapeutic performance of TiO2 are also beneficial for designing other inorganic

sonosensitizers. BP, as an emerging 2D metal-free semiconductor nanomaterial, has attracted broad attentions from W


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Table 2. Summary of the Reported SDT Platforms sonosensitizers

assistances (micro- or nanoparticles)

PpIX MnPpIX

HMON

PpIX

HMON

PpIX

HMON, MnOx

rose bengal

Oxygen-loaded microbubble GO, MSN, Fe3O4 FHMON

rose bengal IR780 ALA DCPH-PNa(I) TiO2 TiO2 TiO2

Au

TiO2 TiO2

Polyion complex micelles GR

TiO2@TiO2−x BP

working mechanisms

performances

Activation of the mitochondrial apoptotic pathway

Au

PMCS MON, CAT

Mesoporous structure of HMONs facilitates sonosensitizer loading Activation of the mitochondrial apoptotic pathway Catalytic O2 generation by MnOx to mitigate hypoxia and facilitate ROS generation Oxygen delivery to tumor sites for TME modulation and enhanced ROS generation Reduced cavitation threshold of US Intratumoral oxygen delivery by chelated FC chains to relieve hypoxia In situ generation of PpIX by quick metabolization of ALA precursor DNA ladder formation and caspase-3 activation US-triggered electron−hole pair generation US-triggered electron−hole pair generation Preventing electron−hole recombination by trapping the sonoexcited electrons Electrostatic adsorption of graft copolymers High electroconductivity of GR facilitates the separation of electrons and holes Oxygen defects facilitate the separation of electrons and holes Formation of Schottky barriers to inhibit electron−hole recombination Porphyrin-like macrocycle with large HOMO−LUMO gap for ROS production Catalytic O2 generation to enhance the cavitation effect for ROS generation

scientific communities in recent years.70,264−266 Owing to its unique physicochemical properties, such as thickness-dependent band gap, efficient singlet−triplet crossing, and desirable biodegradability, this 2D material has been applied in a number of theranostic modalities, such as PTT,267−269 PDT,178,270 chemotherapy,271,272 photoacoustic (PA) imaging,273,274 etc. Very recently, Ouyang et al. first reported that a BP nanosheet could also respond to US and generate ROS subsequently.113 Inspired by the previous surface engineering strategies, Au nanoparticles were also chelated on BP nanosheets for SDT enhancement. Given that the Fermi level of BP (−3.9 eV) is higher than that of Au (−5.1 eV), such an integration facilitated electron transfer from BP to Au, resulting in the formation of Schottky barriers to inhibit electron−hole recombination, thus favoring ROS generation. On account of the unique biodegradability of BP, it is expected that this emerging 2D material will play a more important role in next-generation SDT. Innovation continues in the field. The unique architecture of porphyrins, which confers these organic molecules with US responsiveness, has also aroused chemists’ enthusiasm to fabricate new sonosensitizers by mimicking their 3D geometry and spatial configuration. Pan et al. first constructed metal− organic-framework (MOF)-derived mesoporous carbon nanostructure containing porphyrin-like metal centers (PMCS) for SDT (Figure 24).275 According to the geometry-dependent electrostatic potential profiles, the superior ROS-generating capability of PMCS is closely associated with the porphyrin-like macrocycle in the nanostructure, in which the large gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) facilitates

refs

Antiproliferative effects on human oral squamous carcinoma cells High tumor accumulation, controllable biodegradation Biodegradability, enhanced therapeutic effect on hepatocellular carcinoma Targeted accumulation, enhanced therapeutic effect on U87 tumor xenograft Overcoming hypoxia and improving SDT efficiency High tumor suppression effect and improved survival rate Highly efficient SDT against hypoxic pancreatic cancer, mitigated resistance Mitigated skin phototoxicity, neovascularization inhibition

240 246 249 253 109, 251 110 252 241

Mitigated phototoxicity, enhanced apoptosis in HL60 cells

239

High stability, long-circulation, immunomodulator effects Well-defined mesoporosity, high dispersity High ROS generation capability, complete suppression of tumor growth Enhanced dispersion stability, improved biocompatibility Enhanced sonocatalytic efficiency, tumor eradication without reoccurrence High 1O2 quantum yield, complete tumor eradication, high biosafety Enhanced ROS-generating efficiency, desirable biodegradability, mitigated side effects Intensified cavitation effect, high tumor inhibition efficiency (85%) Accurate tumor positioning, highly efficient tumor ablation without HIFU prestimulation

111 112 255 256 261 263 113 275 277

ROS production. Moreover, in this work, a nanoparticleassisted cavitation process was first visualized by a high-speed camera, further evidencing the cavitation-involved sonosensitization of PMCS. 3.2.3. Nanotechnology-Augmented but Sonosensitizer-free SDT. Back to the mechanisms of sonochemistry, the sudden collapse of bubbles (inertial cavitation) will inevitably create momentary pressure/temperature gradients to initiate ROS production, even in the absence of sonosensitizers. Therefore, the enhancement of inertial cavitation with the assistance of exogenous nanomedicine is an alternative approach to facilitate US-triggered ROS generation, finally improving the therapeutic outcome of SDT, i.e., sonosensitizerfree SDT. The most representative paradigm is TMEresponsive gas-generating nanosystem, which can generate specific gas bubbles (e.g., O2, CO2, NO, etc.) in the tumor region for the amplification of cavitation effect, thus favoring ROS production for SDT augmentation.276 Very recently, we have constructed CAT@MON composite nanosystems to initiate catalytic O2 generation within tumor tissue for HIFU-triggered therapy (Figure 25).277 The CAT encapsulated in the mesoporous framework of MONs is able to catalyze the disproportionation of intratumoral H2O2 to generate O2, which acts as cavitation nuclei to enhance inertial cavitation of HIFU and its consequent physicochemical effects (i.e., localized hyperthermia and sonodynamic ROS generation). Such a catalytic O2-generating nanoreactor enables efficient tumor ablation under a relatively low intensity of HIFU exposure, which is desired in clinical US-based therapeutic modalities. X


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Promoted by recent advances in nanotechnology, large amounts of US-triggered ROS-generating nanoplatforms have been designed to augment the therapeutic efficiency of SDT (Table 2). This emerging therapeutic modality, as we hope, will undergo a next wave of development in the following decade based on the deeper elucidation on its physicochemical mechanism.

However, due to the low mass energy absorption coefficient of tumor tissue, the therapeutic effect of X-ray may be compromised, while increased doses of X-ray radiation may also lead to serious collateral damage. Thus, in this section, we will concentrate on the recent advances in the fabrication of ROSbased nanomedicines to improve the therapeutic outcomes of X-ray-excited RT, hopefully contributing to the medical advances of RT in the future. 3.3.1. Radiosensitization of Tumor by Nanomaterials. Radiosensitization of tumor by exogenous materials (i.e., radiosensitizers) may be a feasible approach to facilitate intratumoral ROS generation and elevate RT efficacy. Although a few organic molecules such as porphyrins have been demonstrated with radiosensitizing properties,287 however, they suffer from rapid degradation and nonspecific distribution in biosystems, which will compromise tumor radiosensitization. This is where the rapidly developing nanotechnology comes into play.286 The emergence of ROS-based nanomedicines has provided advanced strategies to favor RT enhancement. In general, these radiosensitizing nanomedicines can be classified into two categories: (1) nanomaterials containing high atomic number (high-Z) elements with strong X-ray attenuation ability; (2) NO-generating nanosystems responsive to X-ray irradiations for on-demand release of radiosensitizing NO. Based on the quantum physics theory, the energy-transfer processes under X-ray irradiation, such as photoelectric effect, are positively correlated with the atomic number of irradiated matter. Therefore, nanomaterials containing high-Z elements are capable of presenting strong photoelectric absorbance capacities and releasing electrons (photoelectrons and Auger electrons) for subsequent ROS generation. These emerging nanomaterials, such as Au,288,289 Bi2Se3,286,290−294 TaOx,295,296 W-based materials, 297,298 Hf 4+ -contained MOF, 299−301 UCNPs,302,303 etc., can serve as efficient inorganic radiosensitizers to concentrate ionization energy within tumors for intracellular ROS generation, finally improving RT efficacy. For example, Song et al. first prepared ultrathin Bi2Se3 nanosheets with high X-ray attenuation coefficient for efficient tumor radiosensitization.291 Notably, this 2D radiosensitizer can release vital selenium element for reducing the occurrence of liver, prostate, and lung cancers, further benefiting RT. We recently constructed Bi2Se3-embedded MSNs for simultaneous RT sensitization and pH-responsive CDR.290 The synergy between CDR and RT exerted enhanced therapeutic effect against multidrug-resistance (MDR) cancer cells,304 demonstrating that RT can provide a complementary effect to overcoming the limits of conventional chemotherapy. Moreover, Yong et al. also fabricated Gd-containing polyoxometalates (POMs)-conjugated chitosan (GdW10@CS) for promoting tumor radiosensitization (Figure 27).298 High-Z W and Gd atoms in the GdW10@CS possess strong X-ray attenuation capacity for the efficient radiosensitization and ROS generation, while W6+ can also act as an electron acceptor to react with GSH for improved ROS-generating effect. It is noted that electrons emitted from high-Z nanomaterials can not only directly interact with adjacent tumor tissues but also activate another adjacent semiconducting material across the interface to facilitate the motion of charge carriers (i.e., electrons and holes) for a second amplification of ROS generation. This process is accompanied by the sequential energy transfer from X-ray to high-Z nanomaterials and to semiconducting nanomaterials, resulting in elevated ROSgenerating efficiency. As a typical paradigm, Cheng et al. first

3.3. Radiation Therapy (RT)

RT is still one of the mainstream cancer therapeutic modalities in the clinic together with chemotherapy and surgery.278−280 It takes advantage of ionizing radiation to initiate aberrant physicochemical alterations in cancer cells, such as water ionization and consequent ROS generation,95 inducing the breakage of the DNA double strand and finally suppressing tumor progression. Based on the radiation sources, RT can be further classified into external beam radiotherapy (EBRT) and internal radioisotope therapy (IRT).281 As the most common form of RT, EBRT is implemented by the irradiation of external radiation beams such as high-energy X-ray on pathological sites,282−284 while IRT is assisted by endogenous radiation from radioisotopes (e.g., 131I, 90Y, 188Re, 64Cu, etc.) located in pathological sites after systemic administration and tumor accumulation.98 Thus, IRT is competent for the treatment of metastatic tumors.95,285 Given high-energy X-ray is the most common radiation source in current clinical RT, in this review, we will concentrate on the X-ray-excited RT. Since Roentgen’s 1895 discovery of Xray, its mysterious veil has been gradually uncovered by physicists in the past century. The physical processes of X-ray irradiation, such as Rayleigh scattering, photoelectric effect, Compton scattering, etc., have also been systematically elucidated during that period (Figure 26).95 In RT, the

Figure 26. Schematic illustration for the physical processes when nanoparticle is irradiated by X-ray, such as Rayleigh scattering, photoelectric effect, Compton scattering, etc. Reprinted with permission from ref 95. Copyright 2017 John Wiley and Sons.

Rayleigh scattering fails to bring the therapeutic effect of X-ray due to its elastic nature without energy loss. Comparatively, the photoelectric effect is capable of initiating a toxic effect because the ejected photoelectrons can interact with ambient H2O to produce ROS. In addition, the accompanied Auger effect also favors ROS generation by the release of short-range secondary electrons (i.e., Auger electrons). As a classical inelastic interaction, Compton scattering can also transfer partial energy of incident X-ray to ejected electrons for ROS generation. Therefore, when tumor tissues are exposed to X-ray, the generated photoelectrons, Auger electrons, and Compton electrons can react with the surrounding H2O molecules to produce ROS for causing cancer cell death.286 Y


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Figure 27. Gd-containing polyoxometalates (POMs)-conjugated chitosan (GdW10@CS) for treating hypoxic tumors. (a) Schematic illustration for the synthesis and cellular therapeutic mechanism of GdW10@CS. PARP, poly(ADP-ribose) polymerase. (b) Chemical mechanism of GdW10@CSbased RT by attenuating radioresistance and enhancing radiation response. Reprinted with permission from ref 298. Copyright 2017 American Chemical Society.

Figure 28. Integrating high-Z nanomaterials with semiconductors for amplified ROS generation. (a) Schematic illustration for the formation of O2•− and •OH on photoexcited TiO2 nanoparticles (left) and X-ray-activated hybrid Au@TiO2 nanostructure (right). (b, c) TEM images of as-prepared hybrid Au@TiO2 nanostructure at low (b) and high (c) magnifications. (d) UV−vis absorption spectra of DPBF in Au@TiO2 dispersions upon the irradiation of UV (365 nm) or X-ray (2, 5, 10, and 20 Gy), evidencing the X-ray-triggered ROS-generation. (e) Flow cytometry analysis to evaluate ROS generation in DCFH-DA-stained SUM159 cells treated with Au@TiO2 under X-ray irradiation. (f) Flow cytometry analysis in fluorescein isothiocyanate (FITC) channel to evaluate ROS generation in SUM159 cells treated with Au nanoparticles, TiO2 nanoparticles and hybrid Au@TiO2 nanoparticles. Reprinted with permission from ref 289. Copyright 2018 American Chemical Society.

constructed Au@TiO2 hybrid anisotropic nanostructure as an efficient radiosensitizer for treating triple-negative breast cancer (Figure 28).289 Under X-ray irradiation, high-energy electrons emitted from Au nanoparticles can travel for microns in aqueous solutions for ROS production, while the low-energy electrons can only deposit energy within the nanometer vicinity of Au, which enables the strong asymmetric electric coupling between Au and TiO2 at their nanoscale interfaces, resulting in the separation of generated electrons and holes on the surface

of TiO2 without significant recombination, further facilitating ROS generation. This pioneering study applies surface chemistry/physics to regulate the behavior of charge carriers for enhanced ROS-generating capability, which inspires researchers to integrate high-Z nanomaterials and semiconducting nanomaterials for the optimization of RT outcome. The other important participant for tumor radiosensitization is NO-generating nanosystem. As one of the most prominent gas transmitters in biosystems, NO regulates numbers of Z


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Figure 29. X-ray-controlled NO release for on-demand depth-independent radiosensitization. (a) Fabrication and subsequent therapeutic functioning of NO-releasing nanoradiosensitizer (denoted as PEG-USMSs-SNO). (b) NO release from PEG-USMSs-SNO after exposure to varied doses of X-ray. Reprinted with permission from ref 309. Copyright 2015 John Wiley and Sons.

Figure 30. TME modulation strategies for enhancing radiation response. (a) Albumin/polyelectrolyte-coated MnO2 (A-MnO2) nanoparticles for simultaneous O2 generation and pH regulation. (a1) Schematic diagram and corresponding TEM images of MnO2 and A-MnO2 nanoparticles. BSA, bovine serum albumin. (a2) Chemical mechanism of the reaction between MnO2 and acidic H2O2. (a3) Digital photographs of polyelectrolyte-MnO2 nanoparticles (left) and A-MnO2 nanoparticles (right) in various aqueous media. A-MnO2 nanoparticles show better solubility and stability in these media than polyelectrolyte-MnO2 nanoparticles. DDI, doubly distilled; FBS, fetal bovine serum. (a4, a5) Immunohistochemical image of tumor tissue stained with γ-H2AX. Reprinted with permission from ref 311. Copyright 2014 American Chemical Society. (b) Construction of erythrocytemembrane-coated perfluorocarbon (PFC) nanoparticles (PFC@PLGA-RBCM) as artificial RBCs to deliver O2 and enhance radiation response. (b1) Synthetic procedure of biomimetic PFC@PLGA-RBCM. (b2) Blood-circulation curves of bare PFC@PLGA and PFC@PLGA-RBCM in nude mice. DIR, 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl indotricarbocyanine iodide. (b3) Schematic illustration of blood vessel penetration and tumor accumulation of PFC@PLGA-RBCM nanoparticles for TME modulation. Reprinted with permission from ref 314. Copyright 2017 John Wiley and Sons.

biocidal activity.305 Such a NO-mediated biochemical cascade benefits the enhancement of RT to a large extent via multiple pathways, which fascinates scientists to design NO-generating nanosystems for on-demand NO release in tumor region. We first constructed X-ray-controlled NO-releasing nanoradiosensitizer in 2015 by modifying PEG and NO donor (S-nitrosothiol, SNO) on the UCNP@silica nanostructures (USMSs, Figure

physiological activities such as neuronal communication, blood vessel modulation, wound healing, etc.305 More importantly, at relatively high concentrations, NO can serve as an effective radiosensitizer to favor tumor radiosensitization and subsequent ROS generation.306−308 Furthermore, NO can continue to react with generated ROS to yield highly reactive peroxynitrite (ONOO−) molecules with remarkably increased AA


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Figure 31. Mild hyperthermia during PTT for enhancing RT efficacy. (a) Synthetic procedure and oncological applications of MoS2/Bi2S3 composite nanosheets. (b) TEM images of PEG-modified MoS2/Bi2S3 nanosheets. (c) Tumor-growth curves after various treatments as displayed in the figure (n = 6). Reprinted with permission from ref 292. Copyright 2015 John Wiley and Sons.

29).309 Under exogenous X-ray irradiation, the S−N bond of SNO will cleave, leading to NO release for on-demand radiosensitization of tumor. It is expected that more NOgenerating nanoplatforms will be fabricated in the future to promote the improvement of RT outcomes. 3.3.2. RT Enhancement by Tumor Microenvironment (TME) Modulation. A dilemma in the clinical RT is the radioresistance of solid tumors, as a consequence of their hypoxic nature in a multifactorial but interrelated fashion. For example, under X-ray irradiation, DNA radicals (DNA•) can be produced to result in the apoptosis of cancer cells. However, such cytotoxic effects fail to be present under hypoxic conditions, which is mainly attributed to the reduction of DNA• by thiol compounds in hypoxic tumor.95 Moreover, as the hallmark of hypoxia response, the upregulation of hypoxiainducible factor 1 (HIF1) activity can promote the expression of VEGF, while creating pleiotropic effects on tumor cells to counterbalance the promotion of radiation-induced cell apoptosis, further compromising RT efficacy.310 Thus, to surmount hypoxia-associated radioresistance, the modulation of hypoxic TME is desired to reoxygenate tumor and enhance radiation response. In the past decade, various nanoplatforms have been fabricated to relieve hypoxia in RT. In general, these nanosystems can be classified into the following three categories: The first one is O2-generating nanosystems, such as CATloaded nanocomposites296 and MnO2 nanoparticles,311−313 which can catalyze the decomposition of intratumoral H2O2 into O2 for mitigating hypoxia. For example, Song et al. first fabricated CAT-loaded TaOx nanoshells as bionanoreactors and radiosensitizers to enhance RT.296 High-Z Tantalum possesses a high X-ray attenuation coefficient capable of concentrating radiation energy within the tumor, while CAT-catalyzed O2 generation can relieve tumor hypoxia and improve RT efficacy. Moreover, the mesoporous structure of TaOx nanoshells

enables the free diffusion of H2O2 and O2, guaranteeing the high catalytic activity of CAT. In addition, Prasad et al. fabricated albumin/polyelectrolyte-coated MnO2 (A-MnO2) nanoparticles that could react with intratumoral H2O2 and H+ for simultaneous O2 generation and pH regulation (Figure 30a).311 It has been demonstrated that the treatment with AMnO2 nanoparticles lead to the downregulations of HIF1α and VEGF, further promoting hypoxia modulation. Inspired by this work, Yi et al. reported core−shell Au@MnO2 nanoparticles for enhanced RT via favoring tumor reoxygenation.312 The second one is O2-delivering nanosystems, such as perfluorocarbon (PFC)-based nanomaterials,314 hemoglobinloaded nanomaterials315 and oxygen microbubbles,316 which present high O2-loading capability for TME modulation. A recent study by Gao et al. first reported erythrocyte-membranecoated PFC nanoparticles as artificial RBCs to deliver O2 and enhance radiation response (Figure 30b).314 In this hierarchical nanoformulation, PFC serves as a promising oxygen carrier to elevate intratumoral O2 level for enhancing RT, while the coating of the erythrocyte membrane prolongs the blood circulation half-life of the biomimetic nanosystem. In addition to surmounting hypoxia-associated radioresistance, such a strategy may also be beneficial for improving the outcomes of other therapeutic modalities such as PDT and SDT, in which tumor hypoxia is also a key cause of therapeutic resistances. Other O2-delivering materials, such as hemoglobin or oxygenmicrobubble-based composite nanosystems, are commensurate to PFC-based ones in regulating hypoxic TME and enhancing RT efficacy. The third category is photothermal agents, such as Bi2Se3/ Bi2S3-based nanosystems,286,292−294 which can result in mild hyperthermia during PTT to boost the blood flow into the tumor and increase the intratumoral O2 level, thus reducing radioresistance and enhancing RT efficacy. We first fabricated 2D MoS2/Bi2S3 composite nanosheets for synergistic PTT/RT AB


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Figure 32. MoS2 dots with excellent H2O2 reduction and ORR activities for radiation protection. (a) Viability assay of A31 cells to evaluate the dosedependent protective effect of MoS2 dots. (b) Survival curves of mice after different treatments. (c) DNA damage of mice in 1 and 7 days after treatment with Cys-protected MoS2 dots (n = 14 mice/group). *P < 0.05. Reprinted with permission from ref 325. Copyright 2016 American Chemical Society.

(Figure 31).292 As one of the most representative transition metal dichalcogenides, MoS2 nanosheets with favorable photothermal performance have been extensively explored for PTT,317−321 while Bi2S3 with high X-ray attenuation capability can enhance radiosensitization of tumor. The integration of MoS2-based PTT and Bi2S3-based RT presents a synergistic therapeutic effect for tumor eradication. Another example is polyvinylpyrrolidone (PVP)- and selenocysteine (Sec)-modified Bi2Se3 nanoparticles for PTT-enhanced RT.293 The strong NIR absorption ability of Bi2Se3 was utilized for photothermal conversion and subsequent hypoxia modulation, providing a complementary effect in mitigating radioresistance during RT. Such a PTT-augmented RT strategy will be further discussed in the following section for the RT-based synergistic therapy to help readers understand the synergy between the two cancer therapeutic modalities. The above three categories of tumor-reoxygenating nanosystems provide feasible tools to modulate hypoxic TME and enhance RT. It is believed that the development of nanotechnology will further favor the emergence of multifunctional nanoplatforms to overcome hypoxia in RT, finally making evergreater medical advances. 3.3.3. Radiation Protection by ROS Scavenger. The high-energy ionizing radiation during RT can be a doubleedged sword, which not only enables tumor suppression but also leads to inevitable damage to adjacent normal tissues. At the cellular level, the ionizing radiation can induce unavoidable ROS generation in ambient normal cells, resulting in mitochondrial dysfunction, mitotic catastrophe, and activation/inactivation of various proteins involved in the apoptotic process.139 Although the cellular antioxidant defense mechanisms are capable of relieving oxidative stress to a certain extent, however, they fail to rectify all the radiation damage during RT. The dyshomeostasis of intracellular redox status gives rise to symptoms such as nausea, vomiting, fatigue, hair loss, etc., which underscores the need to consider rational strategies for radiation protection. With the rapid development of nanotechnology, large numbers of nanoplatforms with ROS-scavenging capabilities have been fabricated as efficient radioprotectants,322 including (1) inorganic nanozymes such as CeO 2 nanoparticles,84,139,323,324 which present intrinsic SOD-like catalytic activities for scavenging excessive ROS; (2) inorganic electrocatalysts such as MoS2,325 WS2,326 Pt-based alloy,327 etc., which present excellent oxygen reduction reaction (ORR) activities for ROS depletion; and (3) organic nanoparticles containing ROS-scavenging groups, such as melanin nanoparticles,328

which combine physical shielding and chemical quenching effects of ROS for mitigating radiation-induced side effects. As one of the most prevailing candidates among inorganic nanozymes, CeO2 nanoparticles with multiple enzyme-mimicking properties (SOD, CAT, and even oxidase-like activities) have been extensively investigated in the past two decades,131,329−332 of which SOD and CAT-like activities endow them with intrinsic sequential ROS-scavenging performances (i.e., from O2•− to H2O2 to H2O), by reversibly binding oxygen atoms and shifting between the Ce3+ (reduced) and Ce4+ (oxidized) forms. The unique antioxidative property of CeO2 has been extensively explored in radioprotection. A prominent study in 2005 by Tarnuzzer et al. first presented that vacancyengineered CeO2 nanoparticles conferred normal human breast cells with a radioprotection effect.84 In this work, CeO2 treatment resulted in almost 99% protection of normal human breast cells from radiation damage, whereas the same CeO2 concentration showed almost no protection effect on human breast tumor line, MCF-7. Such a selective radioprotective effect of CeO2 nanoparticles is highly beneficial in mitigating radiation damage on normal tissues while guaranteeing RT efficacy on tumors. Moreover, these researchers further demonstrated that the intra- and extracellular pH differences in tumors versus normal tissue may contribute to the selective radioprotective effects. In another two successional reports, CeO2 nanoparticles were also demonstrated to protect the normal lung fibroblast and gastrointestinal epithelium against radiation-induced damage by scavenging excessive ROS.139,323 The significant radioprotective effect of CeO2 nanozyme also inspired the investigations of other inorganic nanomaterials with ROS-scavenging activities for radiation protection. Recently, encouraged by the momentous achievements in electrocatalysis,333 several representative electrocatalysts with excellent ORR activities have also been applied for the depletion of excessive ROS in RT. Zhang et al. first reported Cys-decorated MoS2 dots as highly efficient radioprotectants against ionizing radiation (Figure 32).325 They indicated that the antioxidative property of MoS2 dots could be attributed to their excellent electrocatalytic activities for H2O2 reduction and ORR by facilitating free electron transfer.334 In vivo studies showed that Cys-protected MoS2 dots exhibited nearly 80% urine excretion in 24 h without any significant toxic effects, further demonstrating that such engineered MoS2 dots are biocompatible enough for future radioprotective applications. Alternatively, Bai et al. revealed that ultrasmall WS2 quantum dots could also protect hematopoietic system and DNA from radiation damage by scavenging excessive ROS throughout the AC


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Figure 33. PtPdRh hollow nanocubes for ROS clearance via surface-mediated bond breaking. (a) Synthetic procedure and therapeutic concept of hollow PtPdRh nanocubes. (b) TEM image (b1), HRTEM image, (b2) and corresponding element mapping images (b3) of the hollow PtPdRh nanocubes. (c) Mechanism of surface reactions of hollow PtPdRh nanocubes. (d) ORR activities of PtPdRh and PtPd as a function of O and OH binding energies, indicating that PtPdRh has a much higher activity than PtPd. (e) Combination mode of PtPd-O2 and PtPdRh-O2. Reprinted with permission from ref 327. Copyright 2018 John Wiley and Sons.

Table 3. Summary of Emerging Nanomedicine Strategies To Improve the Therapeutic Outcomes of RT strategies

representative nanomaterials

working mechanisms

Designing new-generation radiosensitizers with ever-stronger X-ray attenuation ability

High-Z nanomaterials, such as Au, Bi2Se3, TaOx, Wbased nanomaterials, MOF with Hf4+, etc. Gasotransmitters, such as NO-generating nanomaterials

TME modulation by reoxygenation to relieve hypoxia and enhance radiation response

O2-generating nanosystems, such as MnO2 nanoparticles, CAT-loaded nanocomposites

Nanomaterials with high Z elements can concentrate radiation energy within tumors NO in relatively high concentrations can serve as an efficient hypoxic radiosensitizer to enhance RT Catalytic generation of O2 by in situ H2O2 decomposition to mitigate hypoxia and facilitate ROS generation O2 delivery by nanomaterials to elevate intratumoral O2 level and relieve hypoxia

Exploring new nanomaterials with intrinsic ROS-scavenging capability for radioprotection

O2-carrying nanosystems, such as PFC-based nanomaterials, hemoglobin-based nanomaterials, oxygen microbubbles Nanosystems with additional photothermal performance, such as Bi2Se3-based nanoplatform Inorganic nanozymes, such as CeO2 Inorganic electrocatalysts, such as MoS2, WS2, Ptbased alloy, etc. Organic nanoparticles containing ROS-scavenging groups, such as melanin nanoparticles

body.326 Analogous to MoS2 dots, WS2 quantum dots also achieved around 80% renal clearance within 24 h post injection. Very recently, Wang et al. have demonstrated the enhanced ORR activities of Pt-based alloy for in vivo clearance of radiation-induced ROS (Figure 33).327 They fabricated PtPdRh hollow nanocubes based on the galvanic replacement reactions, which enable the successful doping of Pt(II) and Rh(III) into Pd lattice to modulate electronic structure and regulate catalytic performance. Compared with Pt monometallic and PtPd bimetallic counterparts, ternary PtPdRh nanocubes show remarkable catalytic ROS-scavenging properties, which is attributed to the chemical activity of the Rh component that

refs

Mild hyperthermia during PTT boosts the blood flow in tumor and increases intratumoral O2 level Intrinsic SOD-like activity to scavenge ROS Intrinsic ORR activities to favor ROS depletion Combination between physical shielding and chemical quenching of ROS

286, 289−303 306, 307, 309

296, 311, 312

314−316

286, 292−294 84, 131, 139, 323, 324 325−327325−327 328

favors ROS adsorption and new active sites formation at a quite low potential. Moreover, the hollow nanostructures of PtPdRh also provide more available active sites and larger surface area than solid counterparts for efficient H2O2 depletion.335,336 Density functional theory (DFT) calculation in this work indicates that the bond breakage of O2•− enables oxygen atoms generation on the surface of PtPdRh, which is responsible for the radioprotective performance. In vivo studies showed enhanced SOD activity, decreased malondialdehyde concentration, and mitigated DNA damages in bone marrow nucleated cells, all together revealing that the hollow PtPdRh nanocubes could protect normal body tissues from radiation-induced AD


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damage. On account of persistent breakthrough being made in the fertile research area of electrocatalysis,337−341 it is believed that more electrocatalysts with excellent ORR activities will be applied as efficient radioprotectants to protect normal tissues from the oxidative damage during RT. Besides inorganic nanozymes or electrocatalysts, organic nanoparticles containing ROS-scavenging groups, such as melanin nanoparticles, have also been explored as biodegradable ROS scavengers for radioprotection. The radioprotective properties of melanin are attributed to the combined physical shielding and quenching effects of cytotoxic ROS.342 Schweitzer et al. proposed that the radioprotection by melanin is a complex interplay between promoted ROS depletion and inhibited ROS generation through the gradual dissipation of Compton recoil electron energy.343 Thus, based on the intrinsic antioxidative performance, such an organic radioprotectant can be applied to help in protecting normal tissues and organs during RT. For example, Rageh et al. first fabricated melanin nanoparticles to serve as ROS scavengers for the protection of hematopoietic tissues.328 It is noted that in-depth mechanistic investigations are still necessary, given that the radioprotectant overdose will lead to an excessive ROS-scavenging effect resulting in the neutralization of the tumoricidal effect of RT in the tumor region. Based on the above discussion, to overcome the intrinsic limitations of RT and optimize its overall therapeutic outcomes, the judicious scheduling of different nanomedical strategies (Table 3) may be of great importance in benefiting the further development of such a conventional but mainstream cancer therapeutic modality in the clinic.

Figure 34. Schematic illustration for the unique biochemical features in TME, such as acidity, H2O2, GSH, glucose, etc. These features act as endogenous chemical stimuli to activate the innate powers of intratumor-delivered nanomedicines for tumor-specific ROS generation. Reprinted with permission from ref 344. Copyright 2018 John Wiley and Sons.

without external energy input, thus surmounting the tissue penetration limitations encountered by physical-irradiationtriggered ROS-generating therapeutic modalities, displaying a greater application potential for next-generation clinical cancer treatment. Such a chemical-stimuli-driven tumor-specific ROS-generating therapeutic modality was termed as “chemodynamic therapy (CDT)” in our 2016 report on TME-activated localized Fenton reaction for cancer therapy.353 Since then, in the past two years, a number of remarkable studies have tried to fabricate CDT-based nanosystems for advanced cancer therapeutics with high tumor selectivity and therapeutic efficiency. In these works, most nanosystems are designed to respond to the intratumoral H+ and H2O2 to favor Fenton or Fenton-like reactions in TME, thereby favoring the generation of highly toxic •OH against tumors. In this section, we will concentrate on recent advances in CDT and elucidate the underlying chemical principles that confer this emerging therapeutic modality with unique merits for future medical advances. 3.4.1. Catalytic ROS Generation by Fenton or Fentonlike Reactions. The demonstration of Fenton reaction can be considered as a milestone in the development of ROS chemistry. In the presence of Fe2+, H2O2 can be decomposed into highly active •OH radicals in a pH-dependent manner,354 accompanied by dramatic elevation of oxidability.355 Such an intriguing phenomenon drives chemists to take advantage of such an oxidability evolution for numerous applications, such as advanced oxidation processes in industry356 or CDT in medicine for catalytic tumor treatment.62 In fact, in cell biology, Fenton reaction is one of the common physiological processes and plays an important role in ROS regulation. The inactivation of intracellular [Fe−S] clusters via O2•−-involved one-electron oxidation reaction enables the release of H2O2 and Fe2+, which is afterward responsible for cellular •OH generation by Fenton chemistry.2 Such a spontaneous process is within the threshold of cellular redox homeostasis and incapable of presenting therapeutic effects.357 In cancer therapy, the introduction of extraneous Fenton agents to favor excessive • OH generation in cancer cells is highly desired to ensure significant therapeutic efficacy.

3.4. Chemodynamic Therapy (CDT)

In cancer therapeutics, numbers of nanomedicines have been designed with unique responsiveness toward ambient stimuli for generating ROS specifically within tumors. In the previous sections, the discussed cancer therapeutic modalities (i.e., PDT, SDT, RT) are based on the exogenous physical irradiations (e.g., UV−vis light, US, and X-ray), which can translate external energy into internal chemical energy of ROS. Although these therapeutic modalities have been developed to provide applicable approaches for cancer treatment, however, they suffer from limited tissue penetration and inevitable damage to normal tissues, which will greatly compromise the therapeutic outcomes. TME has been extensively investigated recently, in which the cellular metabolism and consequent biosynthetic intermediates/products are prominently different from those in normal tissues (Figure 34).344 The unique biochemical features of TME, such as mild acidity,345,346 high GSH concentration,347−349 and elevated H2O2 level,350−352 provide feasible tools for precise discrimination between tumor and normal tissues. Here, a novel but highly attractive therapeutic concept comes into being: if we could utilize these intrinsic biochemical features in TME as endogenous stimuli, to activate the innate powers of intratumor-delivered nanomedicines, by initiating and facilitating specific in situ chemical reactions only within tumorous tissues rather than normal ones, in which these nontoxic nanomedicines or intratumoral chemical substances are transformed into highly cytotoxic ROS against tumors, the therapy will be realized with high therapeutic efficacy and negligible side effect. It should also be noted that, in this therapeutic process, the intratumoral chemical reactions are directly initiated by endogenous chemical energy in TME AE


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Figure 35. Amorphous Fe0 nanoparticles (AFeNPs) responsive to TME for localized Fenton reaction. (a) Synthetic methodology of AFeNPs via a hubble-bubble approach. (b) TEM characterizations of AFeNPs (b1−b3) and iron nanocrystals (FeNCs, b4−b6). TEM images at low (b1, b4) and high (b2, b5) magnifications and their corresponding SAED patterns (b3, b6) were presented. Reprinted with permission from ref 353. Copyright 2016 John Wiley and Sons.

catalytic ROS generation for cancer therapy (Figure 35).353 We first proposed the concept of “chemodynamic therapy” in this report to hopefully elucidate such an emerging therapeutic modality that takes advantage of endogenous chemical energy in TME to drive intratumoral ROS generation. Benefiting from the glassy nature, the amorphous Fe nanoparticles (AFeNPs) showed greatly improved TME (weak acidity)-responsiveness over their nanocrystalline counterparts and thus presented high therapeutic potential. A phenomenological study by Shevtsov et al. reported that the integration of zerovalent Fe with MSNs could facilitate the treatment of glioblastoma multiforme by crossing the blood−brain barrier (BBB) and initiating Fenton reactions,358 further promoting the application of such a “ferrous ions extraction” strategy in CDT. In addition to zerovalent Fe, FePt is also an important nanoagent to facilitate Fe2+ release in TME for therapy. Since the first report of monodisperse FePt nanoparticles in 2000,362 such ferromagnetic nanocrystals with high magnetocrystalline anisotropy and tunable compositional chemistry have created a wave of enthusiasm of scientists to utilize their unique physicochemical properties for therapeutic applications.360 Sun et al. discovered that, compared with face centered tetragonal (fct) phase of FePt that is chemically ordered and highly stable (Fe and Pt atoms form alternating layers stacked along the [001] direction), the chemically disordered face centered cubic (fcc) counterpart (Fe and Pt atoms are randomly positioned) is subject to acidic TME etching for facilitating Fe2+ release and •OH generation specifically in tumor cells.359 Analogous to the aforementioned AFeNPs, the fcc phase of FePt also benefits from their chemically disordered structure that offers reactivity and thereby can also act as a smart Fe reservoir for controlled Fe2+ release specifically within TME. Different from the above pH-responsive self-sacrificing nanosystems, several nanocatalysts can initiate Fenton-like reactions within acidic tumor tissue while maintaining their compositional integrities due to the catalytic nature and thus to favoring •OH generation in a more stable manner. Thanks to the remarkable advances in the field of nanozymes, numerous

However, the direct introduction of Fe2+ into biosystems is counterproductive to achieve expected therapeutic outcomes. On account of the nonspecificity of Fe2+ during blood circulation, these active ions may even lead to severe oxidative damage in noncancerous regions,353 hindering the further development of Fenton-reaction-based CDT. The fast development of nanotechnology leads us to reconsider more feasible strategies to initiate Fenton or Fenton-like reactions specifically within tumor. In general, these strategies can be further categorized into two methodologies: (1) Construction of pHresponsive self-sacrificing nanosystems, such as zerovalent Fe353,358 and FePt,359,360 which can undergo ionization of matrix in acidic TME, leading to the in situ transformation of Fe from the fixed state (i.e., zerovalent Fe and FePt) to their ionic counterparts (i.e., as-released Fe2+ ions), thus to initiate intratumoral Fenton reaction; (2) Fabrication of pH-responsive self-catalytic nanosystems, such as nanozymes as peroxidase mimics (e.g., Fe3O4), which can respond to acidic TME and present peroxidase-like activities accordingly while maintaining their compositional integrities, thereby favoring Fenton-like reactions in a more stable and continuous manner. The former methodology is based on the acidic-TME-triggered dynamic evolution of the compositional chemistry of noncatalytic nanomaterials for the release of catalytic Fenton agents (Fe2+), and the latter is based on the acidic-TME-triggered dynamic alteration of the reaction chemistry of catalytic nanomaterials to selectively enhance Fenton-like reaction activities within tumor, while their intrinsic physicochemical properties remain intact. Localized acidification of Fe metals enables Fe valence elevation from 0 to +2 for ferrous ion extraction from the etched metallic matrix, finally initiating highly cytotoxic •OH generation against tumor. Among different forms of Fe metals, Fe-based amorphous metals and alloys (also be described as metallic glasses, MGs), which feature extremely high reactive nature due to their metastable random structure, have attracted extensive attention from scientific communities in the past few years.361 In our recent work, the unique reaction characteristic of amorphous Fe was also utilized to facilitate tumor-specific AF


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Figure 36. Dual enzyme-like activities of iron oxide nanoparticles (IONPs) for selective ROS generation. (a) Schematic illustration for the pHdependent dual enzyme mimetic activities of IONPs in cellular environment. (b) Digital photograph of colorimetric reactions. Tubes 1−5: H2O2 + TMB in pH = 4.8 buffer with the addition of none (1), 10 μg/mL Fe2O3 (2), 10 μg/mL Fe3O4 (3), 20 μg/mL Fe2O3 (4), or 20 μg/mL Fe3O4 (5). Tubes 6 and 7: H2O2 + TMB in pH 7.4 buffer with the addition of 20 μg/mL Fe2O3 (6) or 20 μg/mL Fe3O4 (7). (c) Digital photograph of bubble reactions after 6 h incubation. Tubes 1−4: H2O2 solution in pH 7.4 PBS buffer with the addition of none (1), Fe2O3 (2), Fe3O4 (3), and CAT (4). (d) UV−vis absorption spectra of TMB and H2O2 dispersions in the presence of Fe2O3 or Fe3O4 nanoparticles in pH 4.8 or 7.4 buffer. (e) Dissolved oxygen concentrations of H2O2 dispersion in pH 7.4 buffer catalyzed by Fe2O3, Fe3O4, or CAT. Reprinted with permission from ref 378. Copyright 2012 American Chemical Society.

condition), thus reaching selectivity and specificity for cancer treatment. An early study in 2013 first reported Fe3O4mediated selective •OH generation for tumor treatment.379 Then, Fu et al. also constructed a FeOx-based nanosystem to initiate lysosomal •OH generation against cancer.380 Recently, we successfully engineered rFeOx into the framework of hollow MSNs (HMSNs) for concurrent TME-specific •OH generation and biodegradation.381 Such an iron-engineered composite nanocatalyst could readily collapse via an “iron-extraction” strategy under a protein-rich environment,382 thus overcoming the low biodegradability of pristine IONPs. The application of IONPs in cancer CDT also promoted the exploration of other iron-free nanozymes with pH-responsive catalytic activities for cancer therapy.383 For example, Cu-based nanoparticles, such as CuS and CuO, were also reported to possess peroxidase-mimicking activities that can initiate Fenton-like reactions through the cycling between Cu+ and Cu2+.384−391 On account of the intrinsic chemical characteristics of Cu element, such as facilitating ATP depletion to inhibit cancer cell proliferation,392 or potentiating the toxicity of some chemodrugs (e.g., tetraethylthiuram disulfide),393 it is expected that Cu-based nanozymes will also attract extensive attention as multifunctional nanoplatforms for efficient cancer therapy.

nanomaterials have been demonstrated with peroxidase-like activities,101,363−369 among which Fe3O4 nanoparticle is the most prominent one and has been extensively explored in CDT.370 Year 2007 marked the booming growth of Fe3O4based nanocatalytic applications when Yan and her co-workers first reported the intrinsic horseradish peroxidase (HRP)-like activity of ferromagnetic nanoparticles.85,371 They demonstrated that Fe3O4 nanoparticles can catalyze the oxidation of peroxidase substrates in the presence of H2O2, leading to a color reaction similar to that of natural peroxidases. Since then, marked breakthroughs have been made in this field,372−377 and the most typical one is Gu and his colleagues’ 2012 elucidation on the pH-dependent dual enzyme mimetic activities of iron oxide nanoparticles (IONPs) in intracellular environment (Figure 36).378 Under neutral pH condition (e.g., cytosol conditions), IONPs could catalytically disproportionate H2O2 into nontoxic H2O and O2, presenting CAT-like activity. Comparatively, under acidic condition (e.g., lysosome conditions), they could decompose H2O2 into highly toxic •OH via Fenton reaction, displaying peroxidase-like activity. Although this work was designed to evaluate the cytotoxicity of IONPs, however, such pH-dependent dual enzyme mimetic activities of IONPs also indicate a significant antineoplastic potential: selective catalytic generation of •OH in tumor tissues (mild acidic condition) rather than normal ones (neutral AG


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Figure 37. Multifunctional nanozyme with four enzymes-like activities for tumor-specific ROS generation. (a) HRTEM image of nitrogen-doped porous carbon nanospheres (N-PCNSs). Scale bar, 100 nm. (b) XPS survey spectra of N-PCNSs. (c) Schematic illustrations for four enzyme-like activities of N-PCNSs. OXD, oxidase; POD, peroxidase. (d−g) Chemical reaction equations and enzyme kinetics of N-PCNSs. The oxidase (d), peroxidase (e), CAT (f), and SOD (g) mimetic activities of N-PCNSs are presented together for comparison. Reprinted with permission from ref 394. Copyright 2018 Nature Publishing Group.

composite polymersomes for regulating •OH-generating process.396 Such reaction systems cotriggered by endogenous chemical stimuli and exogenous physical irradiations may benefit efficient modulation of intratumoral Fenton or Fentonlike reactions, finally enhancing ROS-generating efficiency. 3.4.2. CDT Enhancement by Sequential Catalytic Reactions. The aforementioned nanotechnology in CDT is based on the assumption that the elevated H2O2 concentration in TME is high enough to sustain Fenton or Fenton-like reactions. However, according to tumor biology, the H2O2 level in cancer cells is usually limited under a certain threshold by endogenous cellular antioxidant defense mechanisms,10 which will decrease the therapeutic efficacy of CDT. Therefore, the TME-regulation strategy to upregulate the intracellular H2O2 level is highly desired. Constructing sequential catalytic reactions by initiating additional H2O2-generating reaction(s) prior to the Fenton or Fenton-like reactions is the mainstream methodology in current CDT to surmount the problem of limited H2O2 concentration in TME. The first step of intratumoral H2O2 upregulation by inducing rational catalytic reactions will be favorable for the second step, i.e., Fenton or Fenton-like reactions for •OH generation. Based on the recent remarkable advances in this field, such a stepwise catalytic reaction methodology can be further elucidated into the two following approaches: The first one is encapsulating platinum prodrug and Fenton agent into one single nanoformulation. The as-delivered platinum prodrug can be reduced by overexpressed GSH in TME for the generation of cis-diamminedichloroplatinum (cisplatin), which is capable of activating NOX to catalyze dissolved O2 into O2•−. Then, O2•− can be further converted into H2O2 by intracellular SOD. Finally, the delivered Fenton

In addition to the aforementioned transition metal (i.e., Fe and Cu)-based nanozymes, a few metal-free nanozymes have also been developed in CDT. Very recently, Fan et al. presented an elaborately designed nanozyme, nitrogen-doped porous carbon nanospheres (N-PCNSs), with four enzyme (oxidase, peroxidase, CAT, and SOD)-like activities based on pH variation for tumor-specific ROS generation (Figure 37).394 Such a nanozyme design rationale is inspired from the recent advances in electrocatalysis, which doped nitrogen atoms in the framework of porous carbon to confer this electrocatalyst with enhanced catalytic performance. Under acidic environment (i.e., TME), the as-prepared N-PCNSs present oxidase-like and peroxidase-like activities to facilitate simultaneous oxygen consumption and •OH generation (similar to ORR), thus enabling concurrent tumor starvation and CDT for enhanced therapeutic outcome. Comparatively, under neutral environment (i.e., normal tissue), these nanocatalyst are capable of presenting CAT-like and SOD-like activities that favor ROS depletion (similar to OER in electrocatalysis), which also indicate significant application potentials for antioxidative therapy, where ROS depletion is suggested to maintain intracellular redox homeostasis. Additionally, on account of the spontaneous natures of Fenton or Fenton-like reactions, external physical interventions (e.g., light, US, etc.) have also been introduced in CDT to assist temporospatial control of ROS-generating processes for improved therapeutic outcome. In our recent work, we have constructed UCNP-based composite nanosystem to target mitochondrial DNA for CDT, in which NIR was applied to regulate intramitochondrial Fenton reaction process, further promoting •OH generation (Figure 38).395 Moreover, Li et al. also used US as exogenous trigger to activate Fe3O4-loaded AH


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Figure 38. Light-assisted intramitochondrial ROS generation for enhanced CDT. Synthetic procedures and intracellular therapeutic mechanism of UCNP@SiO2 (UCS) nanosystem coloaded with Fe2+ and Ru2+ complex (UCSRF). APTES, (3-aminopropyl)triethoxysilane. Reprinted with permission from ref 395. Copyright 2017 Elsevier Ltd.

agent catalyzes H2O2 decomposition and •OH generation for initiating the therapeutic effect. This strategy is based on the two endogenous natural enzymes (i.e., NOX and SOD) and the introduced Fenton agent to bridge the entire reaction cascade initiated by the GSH-triggered release of cisplatin. Thus, under the joint functioning of platinum prodrug and Fenton agent, sequential conversion of the chemical states of oxygen is enabled, from initial nontoxic intracellular O2, to ultimate highly cytotoxic •OH in a stepwise manner. As a typical paradigm, Ma et al. first decorated cisplatin prodrug on the surface of IONPs to facilitate intracellular sequential ROS evolution for enhanced CDT (Figure 39).397 The elevated •OH level results in oxidative damage to lipids, proteins, and DNA of cancer cells, inducing apoptosis via the ROS/Cyt C/caspase-3 pathway. Inspired by this work, Dai et al. constructed two types of self-assembled metal-phenolic network nanoparticles (composed of platinum prodrug

polyphenols, PEG polyphenols matrix, and Fe3+) to augment cancer CDT.398,399 They first introduced MPO into such a sequential catalytic system to catalyze additional HClO generation within cancer cells, and thereby to further potentiate a •OH-based CDT outcome.399 Then they also utilized Dox as an additional exogenous stimulus besides platinum prodrug polyphenols to further promote O2•− production and downstream •OH generation for an enhanced CDT effect.398 However, such platinum-prodrug-activated sequential catalytic reactions may suffer from the dynamic variations of the concentrations and catalytic activities of the two endogenous enzymes (i.e., NOX and SOD) in the intracellular milieu. This limitation drives us to consider other feasible strategies to circumvent such a limitation of endogenous enzymes. Here, it is conceived that, if we could directly introduce exogenous enzymes into the reaction system, rather than activate endogenous enzymes indirectly by chemical reactions, the AI


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Figure 39. Engineered composite nanoplatform for sequential catalytic ROS transformation in cancer cells. Schematic illustration for the reaction mechanism, fabrication rationale, and intracellular cascade of cisplatin-prodrug-loaded IONPs. PEI, polyethylenimine. Reprinted with permission from ref 397. Copyright 2017 American Chemical Society.

(Sequential reaction II, chemical catalysis), thus significantly elevating the •OH-generating efficiency. 3.4.3. Chemodynamic ROS Generation by Other Mechanisms. Other nanotechnologies for cancer CDT have also been developed in parallel. Recently, a number of specific organic molecules has also been reported with ROS-generating capabilities, which can respond to specific biochemical triggers and initiate autologous intramolecular structural variations to facilitate ROS generation. Compared with conventional inorganic Fenton agents that take advantage of H2O2 as indispensable substrate, such bioresponsive organic molecules can act as innate ROS sources to favor intracellular ROS generation without the addition of H2O2 and thus to overcome the H2O2 limitation in cancer cells. Among these emerging organic agents, artemisinin and its derivatives are the most representative ones that have been extensively explored in non-Fenton CDT.401 Their unique endoperoxide bridges can undergo reductive cleavage upon Fe2+ activation, leading to significant ROS generation. Based on

H2O2 concentration elevation and subsequent CDT augmentation would be precisely controlled. This strategy can even simplify the H2O2-generation process by judicious selection of one single exogenous while robust enzyme, for example, glucose oxidase (GOD, or GOx),400 to directly catalyze the intrinsic substances in TME (e.g., glucose) into H 2 O 2 intermediates and thus to favor the subsequent Fenton or Fenton-like reactions for CDT. In our recent report, a composite nanocatalyst was constructed by integrating natural GOD and ultrasmall Fe3O4 nanoparticles into the biodegradable dendritic MSN (DMSNs), to facilitate sequential catalytic reactions for TME modulation and CDT augmentation (Figure 40).17 The as-delivered GOD in the composite nanocatalyst could effectively catalyze the depletion of glucose nutrients and in the meantime generate H2O2 in TME (Sequential reaction I, biological catalysis), providing abundant substrate to support subsequent Fentonlike reaction catalyzed by the codelivered Fe3O4 nanozymes AJ


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Figure 40. Tumor-selective nanocatalytic medicine facilitates sequential reactions for TME modulation and CDT augmentation. (a) Synthetic procedures of the GOD-Fe3O4@DMSNs (GFD) nanocatalysts. (b) Dark-field TEM image of GFD nanocatalysts. Scale bar, 50 nm. (c−f) Michaelis−Menten kinetics (c, e) and Lineweaver−Burk plotting (d, f) of Fe3O4 nanoparticles (c, d) and GFD nanocatalysts (e, f). (g) Schematic illustration for the sequential catalytic mechanism of GFD nanoparticles for TME modulation and CDT augmentation. Reprinted with permission from ref 17. Copyright 2017 Nature Publishing Group.

specific sequential reactions for ROS generation within tumor. A representative report in 2014 first showed that the lysosomal acidification of Fe/O cluster could facilitate the activation of artesunate for CDT.402 In this study, they fabricated a

the previous discussion that several Fe-based nanosystems can undergo ionization in acidic TME and release Fe2+, which favors artemisinin activation, the combination of Fe-based nanosystems with artemisinin is applicable to initiate TMEAK


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Figure 41. Linoleic acid hydroperoxide (LAHP) as innate ROS source to favor 1O2 generation. (a) Chemical mechanism, synthetic procedure, and biological effects of LAHP-IONPs (IO-LAHP). (b) UV−vis absorption spectra of 1O2 scavenger before and after successive addition of LAHP and Fe2+. (c) Fluorescence spectra of SOSG before and after the successive addition of LAHP and Fe2+. (d) TEM image of IONPs. (e) Time-dependent release profiles of Fe2+ from the IO-LAHP nanoparticles under different pH values. (f) Tumor sections after treatment process. (g) Sectional TEM images of a healthy (g1) and a treated tumor with LAHP-IONPs at low (g2) and high (g3, g4) magnifications. Reprinted with permission from ref 409. Copyright 2017 John Wiley and Sons.

resultantly produced ROS in conventional Fenton-based CDT, the as-delivered LAHP as an exogenous ROS source is able to largely elevate the intratumoral ROS production and thus exhibit great application potential for next-generation CDT. As an exogenous chemical-stimuli-driven therapeutic modality, CDT confers cancer treatment with high specificity, efficacy, and biosafety (Table 4). It is believed that such an emerging cancer nanotherapeutic modality will undergo a second leap-forward in development in the near future.

sequential reaction nanoreactor by engineering Fe/O cluster and artesunate into HMSNs, to endow such a nanosystem with pH responsiveness for on-demand Fe2+ release and artesunate activation. Based on the recent advances in the biomedical applications of MOFs,403−407 Wang et al. designed core−shell Mn3[Co(CN)6]2@MIL-100(Fe) MOF nanocubes as both artesunate carrier and Fe2+ donor, for pH-responsive artesunate activation and intratumoral ROS generation.408 The success of artemisinin and its derivatives in CDT also promoted the exploration of other types of peroxides to favor chemodynamic ROS generation within tumor. Linoleic acid hydroperoxide (LAHP) is one of the primary products of lipid peroxidation, which can be decomposed into 1O2 in the presence of Fe2+ through the Russell mechanism. Analogous to artemisinin, LAHP can also be developed for cancer CDT by integrating it with Fe-based nanosystems. As a typical paradigm, Zhou et al. fabricated a LAHP-IONPs composite nanosystem (IO-LAHP) to initiate intracellular sequential reactions against cancer (Figure 41).409 The mild acidic TME facilitates the extraction of Fe2+ from the surface of IO-LAHP, leading to the decomposition of LAHP into 1O2 for therapeutic effect. Considering the limited amounts of endogenous H2O2 and

3.5. Controlled Drug Release (CDR)

Chemotherapy, the most conventional cancer therapeutic modality in the clinic,410 suffers from compromised therapeutic efficacy and severe side effects.411−413 To overcome such a predicament, CDR has been developed to take advantage of the unique responsiveness of nanomedicines toward endogenous biological stimuli in TME (e.g., acidity,414 redox,415 enzymes,416 temperature,417 etc.), or exogenous physical triggers (e.g., light,418 US,419 magnetic field,420 etc.), for precision release of chemodrugs in the tumor region, thus improving the treatment outcome of chemotherapy.421−423 AL


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Table 4. Summary of the Representative CDT Platforms catalysts

assistances (drug molecules, nanocarriers)

FePt FeOx

MSN

rFeOx

MSN

amorphous iron nanoparticle (AFeNP) IONP

cisplatin

IONP

LAHP

Fe/O cluster

artesunate, HMSN

Fe3+

artesunate, MOF

Fe3+, polyphenol

Dox, Pt-prodrug polyphenol

Fe3+, MPO

Pt-prodrug polyphenol, PEGpolyphenol UCNP, Ru2+ complex, NIR HFn

Fe2+ nitrogen-doped porous carbon nanosphere (N-PCNS)

working mechanisms

performances

refs

Controlled release of Fe in acidic environment to catalyze H2O2 into •OH pH-responsive catalytic activity of iron oxide to facilitate •OH generation in cancer cells TME-specific Fenton-like reactions to produce •OH inside cancer cells, iron extraction to facilitate degradation Ionization of AFeNPs in acidic tumors to favor on-demand Fe2+ release for localized Fenton reaction Sequential oxygen transformation from O2 to O2•−, H2O2 and • OH catalyzed by NOX, SOD and Fe2+/Fe3+ couples

Fast oxidation and disruption of cellular membranes

359

Lysosome-controlled intracellular ROS overproduction for therapy Concurrent stimuli-responsive catalytic activity and biodegradability Tumor-specific •OH generation, biodegradability, mitigated side effect Tumor-specific sequential ROS conversion to enable fast lipid and protein oxidation and DNA damage Tumor-specific 1O2 generation efficient apoptotic cancer cell death both in vitro and in vivo Selective intracellular ROS generation, low cost, mitigated side effect Enhanced tumor delivery specificity and antitumor efficacy, negligible long-term toxicity

380

Extraction of Fe2+ from the surface of IO-LAHP to accelerate the decomposition of LAHP into 1O2 Lysosome-enabled Fe2+ release from Fe/O clusters to activate the endoperoxide bridges of artesunate for ROS generation pH-responsive Fe3+ release and subsequent Fe2+ generation to activate artesunate for the generation of carbon-centered free radicals and ROS Sequential oxygen transformation from O2 to O2•−, H2O2 and • OH catalyzed by NOX, polyphenol, and Fe3+

381 353 397

409 402 408

398

Sequential oxygen transformation from O2 to O2•−, H2O2 and • OH/HClO catalyzed by NOX, SOD, Fe3+/MPO

Lipid oxidation and DNA damage, prolonged blood circulation and high tumor accumulation, mitigated side effects Effective cancer treatment in vivo, improved survival rate

UCNP cores convert NIR light into UV or visible photons to favor photo-Fenton reaction Oxidase-like and peroxidase-like activities of N-PCNS to catalyze ROS generation under acidic TME

Exogenous/endogenous stimuli cotriggered therapeutic, mitochondria-mediated apoptosis pathway High specificity, significant tumor regression in human tumor xenograft mice models

395

399

394

(III) activation by exogenous physical irradiation and 1O2 generation. In this section, we will present the state-of-the-art studies concerning recent advances in this field and elucidate corresponding fundamental mechanisms underlying ROS responsiveness for therapeutic specificity. 3.5.1. CDR Directly Activated by Endogenous Intratumoral H2O2. Analogous to conventional Fenton CDT, CDR can also be directly activated by overexpressed H2O2. Benefiting from the advances in nanosynthetic chemistry, numbers of H2O2-responsive nanosystems with unique structural, compositional, and morphological characteristics have been fabricated for precision manipulation of the CDR process. Most of these elaborately engineered nanoplatforms are based on organic redox-active functional segments, which will undergo oxidative cleavage of specific intramolecular/intermolecular covalent bonds in the presence of H2O2 to favor on-demand therapeutic molecules activation/release.425−427 Generally, these active segments are grafted on the host polymer chains which can self-assemble into nanoformulations,428−430 capable of favoring passive tumor targeting via the EPR effect in tumor microvascular systems.431 As a typical paradigm, Wang et al. have prepared a redoxresponsive prodrug nanosystem for CDR in 2013,432 by integrating a camptothecin-based topoisomerase I inhibitor 7ethyl-10-hydroxyl-camptothecin (SN38) and a hydrophilic oligomer of ethylene oxide oligo(ethylene glycol) (OEG) via thioether chain connection (OEG-2S-SN38), which is capable of being oxidized by intratumoral H2O2 to favor the hydrolysis of nanocapsules and subsequent release of SN38 within tumor. In another representative work, Xu et al. integrated anticancer drug mitoxantrone (MTO) with PEG to fabricate selfassembled H2O2-responsive polyprodrug nanoparticles for CDR.433 The excessive H2O2 in TME can initiate thioketal bond cleavage in the as-fabricated polyprodrug for MTO

ROS-mediated CDR has been extensively developed recently, accompanied by the emergence of numbers of engineered nanoformulations with functional motifs sensitive to ROS for initiating inner drug release specifically in the pathological region (Figure 42).96,424 From the perspective of chemical principles, current ROS-mediated CDR can be further classified into the following three categories based on their reaction principles and energy conversion: (I) direct activation by endogenous intratumoral H 2 O 2 , (II) activation by endogenous H2O2 decomposition and O2 generation, and

Figure 42. Endogenous biological ROS or exogenous synthetic ROS as chemical triggers for CDR. Reprinted with permission from ref 423. Copyright 2017 Nature Publishing Group. AM


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decomposed into Mn2+ in acidic H2O2 environment to favor the loaded chemodrug release.438−440 Although O2 is also generated in this process, it is still supposed to be categorized as type I ROS-mediated CDR rather than a type II one, because such a process is directly associated with H2O2-mediated disintegration of host MnO2 matrix leading to the free diffusion and release of guest drug molecules, instead of O2 evolution that provides these guest therapeutic molecules with high enough energy to break loose from the host−guest interactions. Since the first demonstration of MnO2 on enhancing chemotherapy response in 2015,441 several reports have presented the fabrication of MnO2-based CDR nanoplatforms in the past three years.442−445 For example, Hao et al. used hyaluronic acid (HA)-functionalized MnO2 nanosheets as TME-responsive nanocarrier to deliver cisplatin for CDR.445 The ultrasensitive responsiveness of MnO2 nanosheets to acidic H2O2 guarantees high efficiency and tumor-specificity of the CDR process, while the decorated HA can reprogram the antiinflammatory, pro-tumoral M2 macrophages into pro-inflammatory, antitumor M1 ones to further mitigate chemoresistance and enhance therapeutic efficacy. The given H2O2 concentration is limited to a certain threshold in cancer cells; sequential reactions have also been developed in CDR for elevated H2O2 level and consequently improved responsiveness. A recent report presented a cascade amplification release nanoplatform (CARN) for significantly enhanced therapeutic efficiency by facilitating intratumoral H2O2 elevation (Figure 44).446 This nanoplatform was fabricated by simultaneously loading H2O2 supplier βLapachone (Lapa) and H 2 O 2 -responsive Dox prodrug (BDox) into block copolymer, poly(ethylene glycol)-poly[2(methylacryloyl)ethylnicotinate] (PEG-PMAN). Lapa released from the composite nanoformulation facilitates H2O2 generation through the catalysis of the NADPH:quinone oxidoreductase-1 (NQO1) enzyme overexpressed in cancer cells. Then, the elevated intracellular H2O2 level triggered the activation of the boronate moiety in the BDox prodrug subsequently, leading to an amplified drug release process. More importantly, the enhanced consumption of reduced NADPH and ATP in this process could mediate varied Pglycoprotein (P-gp)-related pathways to downregulate P-gp expression for preventing drug efflux and promoting nuclear transportation, thus overcoming MDR of cancer cells and improving the therapeutic efficiency of CDR. Such a H2O2-mediated CDR approach can be extended to 3D organic/inorganic bioresponsive implant for localized cancer therapy. Recently Gu et al. have reported two H2O2responsive hydrogels for combined chemotherapy/immunotherapy, by facilitating intratumoral release of chemotherapeutics and immune checkpoint blockade (ICB) inhibitor with distinct kinetics.447,448 In the first piece of work, a H2O2-active linker, N 1 -(4-boronobenzyl)-N 3 -(4-boronophenyl)N1,N1,N3,N3-tetramethylpropane-1,3-diaminium (TSPBA), was cross-linked with poly(vinyl alcohol) (PVA) to endow the asformed composite hydrogel with TME-responsive biodegradability, thus favoring the controlled release of gemcitabine (GEM) and antiprogrammed cell death-ligand 1 blocking antibody (aPDL1). GEM as a ribonucleotide reductase inhibitor can promote an immunogenic tumor phenotype, while aPDL1 enhances antitumor responses;449 thereby, the combination of them exerts a synergistic immunochemotherapeutic effect for the treatment of low-immunogenic tumors that are poorly responsive to ICB.

release within tumor. Moreover, Pei et al. took advantage of the H2O2-responsiveness of boronic ester bonds for intratumoral sequential release of Cyt c and Dox.434 Such a TME-mediated delivery strategy enables the precise control of the spatiotemporal exposure of chemodrugs in the tumor region, thus exerting a great therapeutic potential. Large numbers of nanoplatforms for H2O2-mediated CDR have been designed to cope with different tumor subpopulations for precision cancer therapy. For example, as one of the most common brain tumor subtypes in the central nervous system, glioblastoma features high malignancy and poor prognosis, and its therapy is severely hindered by the BBB435 and immunosuppressive TME [i.e., upregulation of immunosuppressive cytokine especially tumor growth factor β (TGFβ)].436 Qiao et al. first fabricated traceable composite nanoparticles with H2O2-responsiveness to favor simultaneous Temozolomide and small interfering RNA (siRNA) siTGF-β releases for immunochemotherapy of intracranial glioblastoma (Figure 43).437 The integrated angiopep-2 enables the

Figure 43. ROS-responsive nanoparticles for RNA interference (RNAi)-based immunochemotherapy of intracranial glioblastoma. LRP, lipoprotein receptor-related protein; CTL, cytotoxic CD8+ T lymphocyte. Reprinted with permission from ref 437. Copyright 2018 John Wiley and Sons.

nanosystem to cross BBB and accumulate into the glioblastoma region, while intracellular H2O2 can oxidize the boronic acid group of poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (BAP) to facilitate siTGF-β release for TME immunomodulation and chemotherapy enhancement. Such a synergistic immunochemotherapeutic platform by H2O2-mediated CDR and subsequent immunomodulation also provides much inspiration for researchers to design next-generation CDR nanoplatforms for precision cancer therapy. Comparatively, a small number of H2O2-responsive CDR nanoplatforms are based on inorganic redox-active materials. The most representative example is MnO2, which can be AN


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Figure 44. “Cascade Amplification” strategy-based nanoparticles with a sequential release modality for TME modulation and H2O2-triggered drug release. Schematic illustration for the chemical structure (a) and intratumoral chemotherapeutic effect (b) of CARN. Reprinted with permission from ref 446. Copyright 2017 John Wiley and Sons.

In the other report, a triblock copolymer comprising a central PEG block flanked by two polypeptide blocks, which contains redox-active L-methionine (Me) and dextro-1-methyl tryptophan (D-1MT) (designated as P(Me-D-1MT)-PEG-P(Me-D1MT)), was used to fabricate an injectable H2O2-responsive gel depot for CDR (Figure 45).448 Excessive H2O2 in TME enables the oxidation of the sulfether group of Me into sulfoxide/ sulfone, facilitating the hydrophobicity transition of P(Me-D1MT)-PEG-P(Me-D-1MT) hydrogel for inner aPDL1 and D1MT release, thus pertinently inhibiting the immunoinhibitory ligand PD-L1 and suppressing immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) activity for the enhance-

ment of cancer immunochemotherapy. In the two reports, these in situ formed hydrogels are capable of confining inner therapeutic moieties within polymer matrix to prevent the fast permeation of cargoes out of the tumor, while H2O2 activation facilitates the gradual hydrogel disintegration and sustained cargo release for modulating the kinetics of the CDR process. Inorganic composite scaffolds have also been explored with H2O2-responsiveness for CDR very recently. Different from hydrogel, these inorganic “hard” scaffolds were fabricated by engineering a layer of redox-active material on the surface of the scaffold to confer responsiveness.450,451 Wang et al. have modified Ni−Ti layered double hydroxide (LDH) film on the AO


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Figure 45. Polypeptide-hydrogel-based localized drug delivery to modulate immunosuppressive TME and enhance immune checkpoint blockade. (a) Schematic illustration for the ROS-triggered polymeric hydrophobicity transition of P(Me-D-1MT)-PEG-P(Me-D-1MT) copolymer. (b) Biochemical mechanisms of the localized CDR based on the injectable thermosensitive hydrogel. DC, dendritic cell. Reprinted with permission from ref 448. Copyright 2018 John Wiley and Sons.

mechanical strength threshold of the shell, the as-established nanosystems will collapse, accompanied by the O2 extrusion and drug molecules extraction. Here, H2O2 serves as the endogenous biochemical stimulus to activate these composite nanosystems with in situ morphological evolution for CDR. On account of the symmetric geometries of these CDR nanosystems, they are unable to travel for long distances because of counterbalanced stress distribution. Therefore, they could be applied for passive-targeted but on-demand drug release in the tumor region. As a typical paradigm, Chen et al. first encapsulated CAT and cisplatin into PLGA nanocapsules to fabricate a H2O2responsive symmetric nanoplatform for CDR (Figure 46a).453 When intratumoral H2O2 penetrates the PLGA shell and interacts with inner CAT, O2 is generated that facilitates the shell rupture of PLGA nanoparticles, which will accelerate the inner cisplatin release to induce cancer cell apoptosis. Additionally, the reoxygenation of TME can also be beneficial to attenuate hypoxia and overcome MDR, providing a complementary effect to augment the therapeutic performance of as-released cisplatin. Based on this work, these researchers also selected photosensitive MB molecules as model drugs and integrate them into such CAT-loaded symmetric PLGA nanoparticles for H2O2-activated catalytic O2 generation and MB release, thus to favor TME reoxygenation and PDT enhancement (Figure 46b).454

surface of nitinol alloy to fabricate a composite implant with H2O2 responsiveness for simultaneous tumor treatment and antibacterial therapy.452 The Ni2+ in the LDH film can react with intratumoral excessive H2O2 to generate hydroxyl ions (OH−), which will exchange with butyrate ions in the interlayer to facilitate cytotoxic butyrate release. In vitro and in vivo evaluations evidenced that such an LDH-engineered nitinol alloy implant could not only inhibit tumor growth and bacterial infection but also present relatively low toxicity to normal tissues, demonstrating the feasibility of the H2O2-responsive CDR implant to be applied as a robust platform for localized cancer chemotherapy. 3.5.2. CDR by Endogenous H2O2 Decomposition and O2 Generation. Type II ROS-mediated CDR is based on the catalytic H2O2 disproportionation in the presence of CAT or CAT-mimic nanozymes, to promote O2 generation and create a spatial pressure gradient, either for (1) facilitating the in situ rupture of an external shell and subsequent drug release (symmetric CDR nanosystems) or for (2) powering the nanocarrier motion and favoring targeted drug delivery (asymmetric CDR nanosystems). Such two CDR approaches can be implemented by the codelivery of CAT/nanozymes and chemodrugs within a single nanoformulation, providing an extra “driving force” to further facilitate drug release. The first approach is on the basis of the distinct pressure difference (ΔP) between the inner and outer sides of the shell upon catalytic O2 generation. When such a ΔP overwhelms the AP


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Figure 46. H2O2-responsive, O2-evolving symmetric nanoplatforms for CDR. (a) O2-evolving nanoplatforms controlling the cisplatin release and relieving hypoxia for enhanced chemotherapy. (a1) Structure and cellular mechanism of PLGA nanoparticles loaded with CAT and cisplatin. (a2) SEM images indicating the time-dependent morphological evolution of PLGA nanoparticles with or without H2O2/CAT. Scale bars, 100 nm. (a3) Confocal fluorescence images of HeLa cells treated for different time durations (up row), or treated by different agents (middle row), or treated with as-fabricated nanoparticles as visualized in different imaging modes (down row). Scale bar, 20 μm. PMA, phorbol myristate acetate; NAC, Nacetylcysteine. Reprinted with permission from ref 453. Copyright 2014 Royal Society of Chemistry. (b) O2-evolving nanoplatforms facilitating PS release for controlled PDT. (b1) H2O2-responsiveness of the hierarchical nanoplatforms (HAOP nanoparticles), as well as the physicochemical mechanism of loaded MB for intracellular ROS generation. BHQ, black hole quencher; ISC, intersystem crossing. (b2) MB release profiles with or without the addition of H2O2 and CAT. Scale bars, 100 nm. Reprinted with permission from ref 454. Copyright 2015 American Chemical Society.

compositional alteration (i.e., catalytic O2 generation and subsequent separation from the reaction system).458 Due to the asymmetric geometries of these CDR nanosystems, they are capable of rapid motion for long distances because of the asymmetric stress distribution that produces a net resultant force to overcome strong Brownian forces for self-propulsion, analogous to the rocket in the aircraft industry.459 These artificial self-propelled nanomachines can be referred as nanomotors, which have been extensively developed as an emerging research area in recent years.460−470

The second approach to power nanocarrier motion for targeted drug delivery is enabled by the sustained O2 extrusion from the asymmetric nanocarrier framework, endowing such a composite system with continuous recoil force and accelerated velocity of motion (based on the energy and momentum conservation laws when the reaction system is considered as a whole), finally to overcome the restriction of surrounding hydraulic resistance and tissular steric hindrance for improved tumor penetration and enhanced CDR effect.455−457 Here, H2O2 serves as the endogenous biological fuel to drive these nanosystems to the target region by initiating irreversible AQ


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Figure 47. H2O2-responsive, magnetic-field-guided nanomotor for precision CDR. (a) Synthetic procedure of the supramolecular stomatocyte nanomotors. (b) Experimental setup of homogeneous magnetic field, as well as confocal fluorescence images of stomatocyte trajectories in H2O2 solution. Scale bars, 10 μm. (c) Schematic for the magnetic guidance of Dox/Pt-Ni-loaded stomatocytes through collagen gel matrix by a gradient magnetic field. (d) Bright-field image of HeLa cell in collagen gel. Scale bar, 10 μm. (e) Bright field (left) and fluorescent (right) images indicating that the engineered stomatocytes (indicated by the red arrow) could be guided toward a cell by applying external gradient magnetic field. Scale bars, 10 μm. Reprinted with permission from ref 471. Copyright 2016 John Wiley and Sons.

Figure 48. Light-induced 1O2 generation to enable drug release. (a) Chemical structure of Dox prodrug (PPC-TK-Dox) and Dox-SH, as well as the ROS-responsive therapeutic mechanism. (b) Time-dependent, laser-triggered transformation process from PPC-TK-Dox to Dox-SH. (c) Release profiles of Dox from the ROS-activatable Dox prodrug vesicle (RADV) and its ROS-inactivatable counterpart (RIADV) with or without NIR irradiation. (d) Confocal fluorescence images of different groups. Scale bar, 50 μm. (e) Cellular mechanism of NIR-assisted, 1O2-mediated drug release. Reprinted with permission from ref 472. Copyright 2017 John Wiley and Sons.

established tumor tissue model (collagen gel laden with human cervical cancer HeLa cells) to overcome the steric hindrance for efficient Dox delivery. Given a number of nanomotors with various structures have been fabricated in recent years,465 it is expected that more nanomotors will be applied in cancer CDR for precision delivery of chemodrugs.

For example, Peng et al. have designed magnetically actuated stomatocyte nanomotors for cancer CDR, by introducing therapeutic Dox, magnetic Ni, and catalytic Pt into artificial stomatocytes (Figure 47).471 Such synthetic nanomotors are catalytically powered by Pt nanoparticles in the presence of H2O2 and magnetically steered by magnetized Ni in the presence of applied magnetic field, capable of penetrating the AR


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Figure 49. Light-activated 1O2 generation to facilitate hypoxia-responsive anticancer drug release. (a) Synthesis and molecular mechanism of the composite nanoformulation. (b) Cellular mechanism of light-activated, hypoxia-responsive drug release at the cell level. Reprinted with permission from ref 476. Copyright 2016 John Wiley and Sons.

3.5.3. CDR by 1O2 Generation under Exogenous Activation of Physical Triggers. In a few of CDR nanosytems, exogenous physical interactions have also been applied as excitation sources to initiate ROS (generally 1O2) generation, and thus to favor subsequent ROS-responsive drug release (type III CDR).423 Such a CDR modality can be implemented by introducing additional active agents responsive to exogenous physical excitation (such as PSs and sonosensitizers) into the redox-sensitive nanosystems, thereby enabling exogenously controlled drug release within the tumor. For example, Zhou et al. recently fabricated an ROSactivatable Dox prodrug vesicle (RADV) that could respond to exogenous NIR irradiation for localized treatment of metastatic triple-negative breast cancer (Figure 48).472 Such a nanosystem

was fabricated by integrating Dox prodrug PPC-TK-Dox, PEGylated PS pyropheophorbide-a (PPa-PEG), unsaturated 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and cholesterol into one single nanoformulation. The NIR laser irradiation initiates the photosensitization of PPa-PEG for 1O2 generation, which enables the PPC-TK-Dox (“OFF” state) oxidation and Dox-SH (“ON” state) release for localized chemotherapy. Moreover, these synthetic 1O2 species can also oxidize the unsaturated DOPC to improve the permeability of the lipid membrane, further accelerating Dox release. Cao et al. also constructed red-light-activated ROS-sensitive polymeric nanosystems for remote manipulation of CDR, via the selfassembly of ROS-sensitive polymer poly(thioketal phosphoester) (TK-PPE) with amphiphilic copolymer poly(ethylene AS


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Table 5. Summary of the Representative ROS-Responsive CDR Platforms matrixes

functional agents

stimuli

OEG-2S-SN38

SN38

H2 O2

PEG

MTO-based polyprodrug Cyt c, Dox

H2 O2

MSN IONP, BAP

H2 O2

MnO2

siTGF-β, TMZ HA

H2 O2

MnO2

HA, cisplatin

H2 O2

PEG-PMAN

Lapa, BDox prodrug

H2 O2

PVA-TSPBA

aPD-L1, GEM aPD-L1, D1MT

H2 O2

P(Me-D-1MT)PEG-P(Me-D1MT) nitinol alloy

H2 O2

H2 O2

Ni−Ti LDH, butyrate

H2 O2

PLGA

cisplatin, CAT

H2O2, O2

PLGA

MB, CAT

H2O2, O2

artificial stomatocytes

Pt−Ni, Dox

DOPC and cholesterol PEG-b-PCL, TK-PPE

PPC-TK-Dox, PPa-PEG Ce6, Dox

H2O2, O2, magnetic field Light, 1O2

PVA, CP-NI

Dox

Light, 1O2, hypoxia

mesoporous TiO2

docetaxel

US, 1O2

Light, 1O2

working mechanisms

performances

refs

H2O2-triggered thioketal bond cleavage to facilitate nanocapsule hydrolysis and SN38 release H2O2-triggered thioketal bond cleavage in the polyprodrug for controlled release of MTO H2O2-enabled breakage of boronic ester bonds to facilitate sequential release of Cyt c and Dox H2O2-induced oxidization of boronic acid group to facilitate siTGF-β release for immunomodulation TME-responsive disintegration of MnO2 for relieving hypoxia and facilitating HA release TME-responsive disintegration of MnO2 to facilitate HA and cisplatin release Lapa release facilitates H2O2 generation to trigger the activation of BDox prodrug for on-demand Dox release H2O2-induced biodegradation of hydrogel to favor aPDL1 and GEM releases H2O2-enabled oxidation of sulfether group to facilitate hydrophobicity transition and subsequent cargo release OH− generation by the reaction of Ni2+ in LDH film with H2O2 to exchange with butyrate ions in the interlayer H2O2 decomposition and O2 generation catalyzed by CAT to facilitate PLGA shell rupture and cisplatin release H2O2 decomposition and O2 generation catalyzed by CAT to facilitate PLGA shell rupture and MB release H2O2-powered, magnetic-field-guided navigation of stomatocyte nanomotor

Tumor redox heterogeneity responsiveness, 100% drug loading efficiency Prolonged blood circulation, efficient tumor targeting and penetration Dual drug codelivery to initiate mitochondrial apoptosis and DNA fragmentation Regulating immunosuppressive TME and prolonging the survival lifetime of glioma-bearing mice Mitigated chemoresistance, targeted delivery, cell phenotype reprogramming Mitigated chemoresistance, TME-responsiveness, synergistic therapeutic effect “Cascade Amplification” effect for TME-specific drug release, inhibition of P-gp for enhanced nuclear transportation of Dox Enhanced immunogenic phenotypes, promoted regression of B16F10 melanoma and 4T1 breast tumor Inhibition of PD-L1 and suppression of IDO activity to enhance cancer immunochemotherapy

432

Thioketal group of PPC-TK-Dox prodrug is oxidized by ROS to facilitate Dox-SH release Light-induced photodynamic 1O2 generation by Ce6 to enable TK-PPE degradation and subsequent Dox release Hypoxia-enabled hydrophilicity transformation of CPNI to accelerate nanoformulation disintegration and Dox release US-triggered sonodynamic 1O2 generation by TiO2 to induce oxidative cleavage of thioketal linker for docetaxel release

Simultaneous tumor treatment and antibacterial therapy, low toxicity to normal tissues, localized therapeutic modality Improved therapeutic efficacy, reduced systemic side effect

433 434 437 441 445 446

447 448

452

453

Hypoxia modulation, therapeutic specificity

454

Deep tumor penetration, remote temporospatial control, directional regulation

471

Remote control, efficient inhibition of triple-negative breast cancer Remote control, significant therapeutic effect

472

Remote control, high antitumor potency

476

Deep tissue penetration, high drug loading efficiency, mitigated drug leakage

477

473

therapeutic agents to directly induce cancer cell damage by upregulating intracellular oxidative stress (PDT process) but also act as indirect triggers to initiate drug release by augmenting hypoxia (CDR process), perfectly coordinating unnecessary competition between parallel reactions in the previous examples, in which 1O2 was consumed in both the oxidative stress upregulation (as therapeutic agents in PDT) and prodrug activation (as direct chemical triggers in CDR) simultaneously, presenting attractive therapeutic potential in the clinic. In addition to light, US has also been applied to assist 1O2 generation and subsequent redox-responsive drug release. Shi et al. first fabricated an US-triggered 1O2-generating CDR nanosystem by encapsulating docetaxel into an envelope-type mesoporous TiO2 nanoparticle, followed by β-cyclodextrin attachment on the surface to block the mesopores.477 Under US treatment, 1O2 can be generated via sonosensitization of mesoporous TiO2, leading to oxidative cleavage of thioketal linker and the subsequent liberation of the β-cyclodextrin gatekeeper, thus favoring inner docetaxel release. On account of the intrinsic high tissue-penetrating nature of US, such a USinitiated CDR approach may play an important role in the treatment of deep-seated tumors.

glycol)-b-poly(ε-caprolactone) (PEG-b-PCL), accompanied by the encapsulation of Ce6 and Dox.473 Under 660 nm red light irradiation, 1O2 was generated by Ce6 to initiate the oxidative cleavage of a thioketal linker, resulting in the size shrinkage of the polymer core, thus to favor inner Dox release. Such a lighttriggered CDR modality with remote temporospatial operability provides a feasible clinical option for localized cancer chemotherapy.474,475 In these reports, the light-activated 1O2 generation is an oxygen-consuming process, which will lead to the formation of a localized hypoxic environment (synthetic hypoxia) and consequently the accentuated intrinsic oxygen deficit in TME (natural hypoxia). Such a hypoxia augmentation can also be utilized to activate hypoxia-sensitive nanosystems for CDR. A recent report by Qian et al. presented a light-triggered hypoxiaresponsive nanocarrier for simultaneous PDT and chemotherapy (Figure 49).476 PS-containing conjugated polymer (CP) was grafted with hypoxia-sensitive 2-nitroimidazole (NI) to prepare hydrophobic CP-NI as an active matrix of the nanosystem, which can be converted to its hydrophilic counterpart in the hypoxic environment following photodynamic 1O2 generation, accelerating the disintegration of the nanoformulation and the release of encapsulated Dox. In this paradigm, the synthetic 1O2 species not only serve as AT


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The development of ROS-mediated CDR provides advanced tools to enable precise drug release within tumors based on the redox-responsiveness of nanomedicines (Table 5). It is expected that such an emerging therapeutic modality will play a more important role in improving the therapeutic efficacy of chemotherapy. 3.6. Synergistic Therapy

The diversity and complexity of tumors make it ever-difficult for humans to win in the long march against cancer.98,478,479 Despite the fact that enormous achievements in the fields of ROS science and oncology have been made in developing advanced redox therapeutic strategies for cancer treatment (PDT, SDT, RT, CDT, CDR), however, a single therapeutic modality may still not be competent enough to fully achieve our therapeutic expectations due to the predicament that the heterogeneous tumor tissue may contain specific cancer cell subpopulations that are resistant to the therapeutic effect of monotherapy.480 For example, although extensive efforts have been invested in designing applicable CDR nanoplatforms for precision cancer chemotherapy, MDR of tumor is still an unavoidable issue that largely compromises the effectiveness of chemotherapy.481,482 Radioresistance of solid tumors also undermines the therapeutic efficacy of ionizing radiation in clinical RT and leads to recurrence and even metastasis.310 Therefore, to overcome these obstacles in cancer treatment, the current trend in clinical oncological research has gradually shifted from concerns on monotherapy to multimodal synergistic therapy for improved treatment efficacy.98 Such a combined strategy is established on the recent advances in demonstrating the interdependent relationship between nanomaterials and their stimuli-responsive therapeutic effects that contribute to the gradual amalgamation of different therapeutic modalities, which can be elucidated based on the following considerations: (1) One single exogenous physical irradiation, or endogenous chemical stimuli, can initiate the simultaneous functioning of dual/trimodal therapeutic modalities. For instance, NIR laser irradiation is capable of initiating photosensitization of PSs-loaded UCNPs to facilitate ROS generation for deep PDT, as well as leading to localized hyperthermia of photoabsorbing agents with photothermal-conversion capabilities for PTT; moreover, such a localized redox upregulation or temperature elevation can also serve as chemical/physical trigger to facilitate drug release from nanocarriers for CDR.483 (2) A number of specific pristine nanomaterials with unique structural/compositional characteristics can also respond to multiple physicochemical activations for synergistic dual/ trimodal therapeutic modalities. For example, semiconducting BP nanosheets with unique band structure, high photothermal conversion efficiency, and negatively charged topological surface are able to respond to UV−vis, NIR, and pH for concurrent PDT, PTT, and tumor-specific CDR, respectively.484 (3) Cooperative augmentation between several specific monotherapies can lead to superadditive (namely “1 + 1 > 2”) therapeutic effects that are stronger than any monotherapy or their theoretical combination.98 Typically, PDT and RT are also capable of initiating immunoregulatory cascades in biosystems, which favors their combination with immunotherapy (i.e., photoimmunotherapy and radioimmunotherapy) for enhanced therapeutic outcome of cancer (Figure 50).160,485 Therefore, in this section, recent advances in nanotechnology-augmented multimodal synergistic therapy will be

Figure 50. ROS-based synergistic therapy. PDT and RT can not only facilitate intratumoral ROS generation by photosensitization and radiosensitization but also present immunostimulatory effects for remote and systemic anticancer immunomodulation. The combination of PDT/RT with immunostimulants in immunotherapy [e.g., toll-like receptor (TLR) ligands, cytokines, etc.] is an effective strategy to integrate their intrinsic individual merits (localized or systemic therapy) and common advantages (immunoregulatory effect) for significant superadditive therapeutic effects. BCG, bacillus calmetteguerin; MCWE, mycobacterial cell-wall extract; SPG, schizophyllan; CP, corynebacterium parvum; GMCSF, granulocyte-macrophage colony-stimulating factor; GCSF, granulocyte colony-stimulating factor; TNFα, tumor-necrosis factor-α. Reprinted with permission from ref 160. Copyright 2006 Nature Publishing Group.

discussed in a comprehensive way to clarify their underlying mechanisms that underpin the significant improvements in cancer therapeutic outcomes. Given that CDR-involved synergistic therapy has been presented in the previous section, here we will concentrate on the four ROS-generating modalities (PDT, SDT, RT, and CDT)-based synergistic therapy as well as their corresponding multifunctional therapeutic nanomedicines, hopefully benefiting readers to have a better understanding on the joint efforts that have been made in the past few years in contributing to this evolving field. 3.6.1. PDT-Based Synergistic Therapy. As one of the most developed ROS-generating therapeutic modalities, PDT has been extensively explored to be integrated with other cancer therapeutic modalities (e.g., RT, PTT, CDR, immunotherapy, etc.) based on their interdependent relationships, either to overcome the intrinsic limitations of PDT (poor tissue penetration and severe oxygen reliance) in clinical applications or to provide a complementary effect for benefiting other therapeutic modalities and thus to achieve cooperative augmentation of therapeutic outcomes against cancer. Based on the recent developments in deep PDT that takes advantage of enhanced tissue-penetrability of light irradiations (e.g., NIR, X-ray) used in other therapeutic modalities (RT, PTT) for PSs activation, a combined strategy can be accomplished by one single engineered nanoplatform under one single irradiation. For example, we first integrated a scintillator (SCNP) with a semiconductor (ZnO) to fabricate a composite therapeutic nanosystem (SCNP@SiO2@ZnO-PEG) AU


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Figure 51. PDT-based synergistic therapy. (a) PDT/RT synergistic therapy. (a1) Synthetic procedure of SCNP@SiO2@ZnO-PEG nanoparticles (SZNPs). MPTS, (3-mercaptopropyl) trimethoxysilane. (a2) Physicochemical mechanisms for PDT/RT synergistic therapy. Reprinted with permission from ref 486. Copyright 2015 John Wiley and Sons. (b) PDT/PTT synergistic therapy. Schematic illustration for the synergy of simultaneous PDT and PTT by one single NIR irradiation. FL, fluorescent. Reprinted with permission from ref 501. Copyright 2018 John Wiley and Sons. (c) Synergistic PDT/immunotherapy. Schematic illustration for the biological mechanisms of cancer immunoregulation by integrating NIRmediated PDT with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade. TCR, T cell receptor. Reprinted with permission from ref 515. Copyright 2017 American Chemical Society.

artificial “nano-RBCs” for amplified synergistic deep PDT and PTT by one single NIR irradiation (Figure 51b).501 The asloaded IR780 in perfluorooctyl bromide nanoliposomes can act as both PS and photothermal agent under NIR excitation to favor PDT and PTT simultaneously based on its high 1O2 quantum yield and photothermal-conversion efficiency. Immunotherapy is gaining momentum in oncology,502−511 which orchestrates the body’s potent immune system to target and eradicate cancer cells, resulting in systemic and durable antitumor immunity.512,513 Given the intrinsic immunostimulatory nature of PDT, the two therapeutic modalities can be integrated together to augment immunotherapeutic effects. More importantly, the combination of exogenously triggered PDT with endogenously triggered immunotherapy integrates their individual advantages in both their intrinsic characteristics (PDT: localized and focused; immunotherapy: remote and systemic) and therapeutic mechanisms (PDT: ROS generation for chemical tumor destruction, immunotherapy: immune responses for biological tumor eradication), finally elevating the ultimate systematic therapeutic efficacy of cancer. A preclinical study in 2015 first indicated that PDT in conjunction with synthetic long peptide vaccination could result in tumor eradication by favoring the local tumor ablation and the systemic CD8+ T cell response.514 Subsequently, Xu et al. constructed a UCNP-based composite nanosystem (UCNPCe6-R837 nanoparticle) in combination with cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) checkpoint blockade for synergistic PDT and immunotherapy of colorectal cancer (Figure 51c).515 The photodynamic effect by NIR-

for X-ray-activated RT and deep PDT with diminished oxygen dependence (Figure 51a).486 Under X-ray irradiation, the downconverted UV fluorescence from the SCNP core initiates the formation of electron−hole pairs in semiconducting ZnO coatings, facilitating subsequent cytotoxic •OH generation (PDT) independent of intratumoral oxygen level. Moreover, the intrinsic strong X-ray attenuation capability of the high-Z element (such as Ce) in SCNP also favors ROS generation for inducing radiation damage of tumor (RT). Such an integration between RT and PDT in one single therapeutic process is able to overcome their inherent shortcomings in parallel, such as tissue penetration limitation and oxygen dependence in PDT, as well as radioresistance of tumor in RT, presenting a complementary effect for improving the therapeutic efficacy of cancer. In addition to X-ray, NIR can also initiate parallel therapeutic processes: PDT and PTT. As a compelling therapeutic modality with low cost and mitigated side effects, PTT has been extensively investigated in recent years, promoted by a blooming growth in the number of photoabsorbing agents with desirable photothermal-conversion performances for efficient hyperthermia ablation of tumor.487−496 The synchronous initiations of PDT and PTT by one single NIR irradiation can be achieved by taking advantage of their therapeutic mechanisms that are different from but complementary with each other in contributing to the ultimate antineoplastic effect, i.e., ROS-induced oxidative stress (chemical mechanism) and hyperthermia-induced tumor ablation (physical mechanism).497−500 We recently reported a mitochondria-targeted AV


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Figure 52. PDT/CDR synergistic therapy for tumor eradication. (a) Photoactivable multi-inhibitor nanoliposome (PMIL) for tumor-focused, spatiotemporally synchronized combination therapies. (b) Chemical structures of XL184 and BPD, as well as the synthetic diagrams of the inner XL184-loaded nanoparticles (NP[XL184]) and outer BPD-loaded lipid film. DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)200]; DPPC, 1,2-dipalmitoyl sn-glycero-3-phosphocholine; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane. (c, d) Schematics and representative cryoelectron microscopy images of NP[XL184] and PMIL. Scale bars, 50 nm. Reprinted with permission from ref 518. Copyright 2016 Nature Publishing Group.

ROS generated in the PDT process can not only elevate intracellular oxidative stress for directly exerting a therapeutic effect but also act as an active intermediate to initiate a second chemical cascade for benefitting CDR.517 Therefore, the combination of PSs and chemodrugs in one single ROSresponsive nanoformulation enables the cooperation between PDT and CDR for stepwise cancer therapy, where the photoexcited ROS in the first step favors subsequent drug release in the second step. As a typical paradigm, Spring et al. introduced a photoactivable multi-inhibitor-loaded nanoliposome (PMIL) that confers photocytotoxicity as well as the suppression of treatment escape pathways (Figure 52).518

triggered UCNP-Ce6-R837 nanoparticles facilitates ROS generation and consequent redox upregulation to induce direct tumor destruction, while the produced tumor-associated antigens can serve as an adjuvant to potentiate antitumor immune responses under the assistance of a CTLA-4 checkpoint blockade. A very recent report integrated PpIX with immune checkpoint inhibitor 1-methyltryptophan in one single nanosystem for inhibiting tumor recurrence and metastasis.516 ROS generation by photosensitization facilitates caspase-3 expression and subsequent 1-methyltryptophan release, leading to the activation of CD8+ T lymphocyte for enhanced immunotherapeutic effect. AW


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Figure 53. MnO2-based nanoplatforms to modulate TME and enhance PDT-based synergetic therapy. (a) 2D MnO2 nanosheets anchored with upconversion nanoprobes (UCSs) for TME-specific, oxygen-elevated synergetic PDT/RT. (a1) Chemical interaction between the nanosystems (UCSMs) and intratumoral stimuli (H2O2 and H+) to facilitate hypoxia attenuation and PDT/RT enhancement. UCL, upconversion luminescent. (a2) TEM images of as-prepared UCSMs. Reprinted with permission from ref 523. Copyright 2015 John Wiley and Sons. (b) Albumin-MnO2 nanoparticles as dissociable nanocarriers for TME-responsive, oxygen-elevated synergetic PDT/chemotherapy. (b1) Scheme for the synthetic procedure and pH-specific decomposition nature of HSA-MnO2-Ce6&Pt (HMCP) nanoparticles. (b2) TEM image of highly dispersed HMCP nanoparticles. (b3) In vivo fluorescence images of 4T1 tumor-bearing nude mice in different groups at varied time points, as well as ex vivo fluorescence images of major organs and tumors dissected from those mice. HC, HSA-Ce6; HCP, HSA-Ce6&Pt. Tu, Li, Sp, Ki, H, and Lu represent tumor, liver, spleen, kidney, heart, and lung, respectively. (b4) Scheme for the TME-responsive dissociation of HCMP. HP, HSA-Pt. Reprinted with permission from ref 524. Copyright 2016 John Wiley and Sons.

Exogenous NIR light activates benzoporphyrin derivative (BPD) to generate ROS within tumor microvasculature and parenchyma, which favors sustained release of cabozantinib (XL184) for the inhibitions of both VEGF and MET signaling pathways. An alternative work by Yang et al. took advantage of the photosensitization of Ce6 to favor ROS-induced nanocarrier disintegration and subsequent Dox release, providing a complementary chemotherapeutic effect for enhancing the PDT outcome.519 Moreover, Kim and his co-workers constructed two nanosystems for synergistic PDT/CDR, by taking advantage of 1O2-mediated disassembly of core−shell nanosystems in the presence of visible light to facilitate 1O2 and Dox release.520,521 The previous section on light-triggered, ROS-mediated cancer CDR (3.5.3) has also discussed the synergy between the two therapeutic modalities for improving the therapeutic efficacy. Considering that PDT is an oxygen-consuming process, hypoxic TME modulation by reoxygenation is highly desired to

guarantee its ROS generating efficiency and downstream therapeutic effect. Moreover, for other therapeutic modalities such as RT and chemotherapy, where hypoxia leads to radioresistance/chemoresistance that may compromise their therapeutic outcome, TME modulation to attenuate hypoxia is also a feasible approach to significantly enhance their therapeutic responses.311,441 Therefore, when PDT is integrated with RT and/or chemotherapy for synergistic cancer therapy, the single reoxygenation of TME will favor the simultaneous enhancement of multiple paralleled therapeutic processes. For example, MnO2 as a typical self-sacrificing O2elevating agent can respond to acidic H2O2 in TME for in situ O2 generation.522 We first integrated MnO2 nanosheets with UCNPs to take advantage of such a chemical characteristic for concurrent pH-/H2O2-responsive O2-elevating synergetic PDT/RT (Figure 53a).523 In this work, indirect ROS transformation took place from pathologic H2O2 to intermediate O2 by MnO2, and to cytotoxic 1O2 by PDT/RT AX


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Figure 54. PpIX and Dox coloaded biodegradable HMONs (Dox@HMONs-PpIX) for synergistic SDT/chemotherapy of hepatocellular carcinoma. (a) Synthetic procedure of Dox@HMONs-PpIX and its subsequent oncological application. BTDS, benzothiadiazides. (b) Schematic of ROS generation by HMONs-PpIX-RGD with US treatment. (c) ESR spectra of 1O2 trapped by 2,2,6,6-tetramethylpiperidine (TEMP) in different dispersions with/without the US treatment. (d) Time-dependent SOSG fluorescence intensity of HMONs-PpIX-RGD after US treatment. (e) Relative fluorescence intensity of SOSG in different groups as displayed in the figure. Reprinted with permission from ref 249. Copyright 2018 John Wiley and Sons.

such two paralleled therapeutic processes simultaneously, i.e., sonochemistry for initiating SDT, and the other physical effects for enhancing chemotherapy. More importantly, a significant piece of research in 2013 revealed that SDT could enhance chemotherapy response by facilitating cellular internalization of chemodrugs, activating mitochondrial apoptotic pathways and upregulating the expressions of ATP-binding cassette transporters such as P-gp.526 Thus, the combination of SDT with chemotherapy is highly recommended for future clinical translation based on their simultaneous and cooperative functioning. In light of such a synergy, Wan et al. fabricated HP and Dox coloaded nanomicelles for concurrent SDT/chemotherapy of MDR human breast cancer.527 After US treatment, ROS could be generated via sonosensitization of HP to induce mitochondrial damage and subsequent Cyt c release, which is capable of activating apoptosis pathways. Additionally, the P-gp level could also be upregulated in this process to overcome MDR for enhancing chemotherapy. In an alternative work, Liu et al. also utilized such a multifunctional nanosystem for synergistic treatment of hepatocellular carcinoma (HCC),528 one of the deadliest malignancies worldwide in recent years.529 Recently, we constructed a biodegradable nanoplatform to integrate SDT and chemotherapy for synergistic HCC treatment, by covalently anchoring PpIX within the mesopore of HMONs, followed by Dox loading for chemotherapeutic effect (Figure 54).249 The exogenous US excitation enables efficient 1O2 generation to impart oxidative damage on tumors, while the endogenous GSH interaction favors biodegradation of HMONs for intratumoral Dox release. Synergistic inhibition on HCC growth has been manifested both in vitro and in vivo (84.7% inhibition rate), demonstrating the synergistic effect between SDT and chemotherapy. Temperature elevation of biological tissues is an additional and immediate effect of US, which can be further enhanced by sudden collapse of bubbles in an inertial cavitation process.237

treatments. Such a synergy of endogenous H2O2 initiation for TME modulation and exogenous NIR/X-ray excitation for synergetic ROS generation contributes to the significant augmentation of ultimate therapeutic efficacy. Moreover, Chen et al. also utilized MnO2-based nanoparticles as pH-/H2O2-responsive dissociable agents to modulate tumor hypoxia for enhancing PDT/chemotherapy (Figure 53b).524 They successfully encapsulated Ce6, cisplatinum prodrug c,t,c-[Pt(NH3)2-(O2CCH2CH2COOH)(OH)Cl2] (cis-Pt(IV)SA), and biomineralized MnO2 nanoparticles into human serum albumin (HSA) to fabricate an intelligent multifunctional HSA-MnO2−Ce6&Pt (HMCP) nanoplatform for optimized antitumor effect. The inner MnO2 component can be disintegrated by intratumoral acidic H2O2, which not only facilitates massive O2 generation to attenuate hypoxia and benefit photodynamic ROS generation but also favors gradual dissociation of these synthetic nanoparticles into individual albumin particles of sub-10 nm in diameter for improved intratumoral diffusion and enhanced chemotherapy. Inspired by this work, Yao et al. constructed CeO2-based nanomedicine to modulate TME and enhance synergistic PDT/chemotherapy.525 3.6.2. SDT-Based Synergistic Therapy. As an emerging redox-regulating therapeutic modality, SDT has also been integrated with other therapeutic protocols, such as chemotherapy and US hyperthermia, for cooperative augmentation of anticancer efficacy. Such a combined strategy is based on the versatility of US, whose multiplicity in the interactions with tissues makes these US-mediated therapeutic modalities capable of integrating with each other. For example, acoustic cavitation by US treatment can lead to several downstream effects in addition to sonochemistry, such as acoustic streaming, shock waves, and liquid microjets, which will facilitate the tissue penetration of chemodrugs (an effect termed sonophoresis).237 Therefore, when SDT is integrated with chemotherapy for synergistic cancer therapy, one single US treatment can favor AY


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thus favoring the ROS-generating process; (4) the immunoregulatory potential of SDT can also be explored in detail, which may be developed as combined SDT/immunotherapy if the immunomodulation effect of SDT is potent enough to exert therapeutic effects. On account of the deeper tissue penetration of US than that of light, SDT as an emerging redox-regulating therapeutic modality will play a more significant role in nextgeneration cancer treatment. 3.6.3. RT-Based Synergistic Therapy. The clinical outcome of RT is still not satisfactory enough to make it an optimal cancer treatment option, as a result of its ineffectiveness against hypoxic solid tumors and distant metastases, which seriously restrict the ever-broader application of RT. Nanotechnology has provided unprecedented opportunities to overcome such a predicament by, for example, integrating other therapeutic modalities with RT to provide complementary effects for improving therapeutic efficacy while mitigating side effects. Generally, these combinations for synergy in RT-involved combinational therapeutic outcomes can be summarized as the following three strategies: The first strategy is integrating RT with chemotherapy to overcome the radioresistance of malignancies. Chemotherapy has been evidenced to be capable of inhibiting the self-repair of damaged DNA during RT, as well as promoting cell polarization toward the radiosensitive phenotype.295 Therefore, such a cooperation between chemotherapy and RT can significantly improve the therapeutic efficacy of cancer.531 In our early work in 2013, a rattle-structured multifunctional nanosystem was fabricated by loading cisplatin into UCNP@ SiO2 nanoparticles for synergetic RT/chemotherapy.303 Here, cisplatin was applied both as a chemodrug and as a radiosensitizer to confer enhanced therapeutic performance. In vivo experiments on HeLa-tumor-beared balb/c nude mice further demonstrated that the as-designed nanosystem could provide higher therapeutic efficacy than the individual therapeutic protocols. Moreover, Song et al. constructed an all-in-one therapeutic nanoplatform based on hollow TaOx for simultaneous drug delivery and enhanced RT. 295 The mesoporous shells and large cavities of hollow TaOx guarantee the efficient loading of 7-ethyl-10-hydroxy-camptothecin (SN38), a hydrophobic chemotherapeutic drug, to favor the chemotherapeutic process and RT augmentation. By means of radiosensitization of a high-Z Ta element to deposit X-ray energy inside tumors, as well as SN38-induced cell cycle arrest into a radiation-sensitive phenotype, such a composite nanoplatform also presented remarkable synergistic therapeutic outcomes both in vitro and in vivo. The second one is integrating RT with PTT to overcome hypoxia-associated radioresistance by facilitating TME reoxygenation. As discussed in the previous section, the mild hyperthermia during PTT is capable of boosting blood flow into tumor tissue, resulting in elevated O2 level and mitigated hypoxia-associated radioresistance.293,532 In the past several years, large amounts of nanosystems with both X-rayattenuation capability and photothermal-conversion performance, have been designed for simultaneous RT/PTT. We first constructed a core/satellite nanoplatform for combined RT and PTT in 2013, by decorating ultrasmall CuS nanoparticles onto the surface of silica-coated UCNPs.302 Such an engineered nanosystem could not only convert NIR into heat efficiently based on the photothermal property of CuS533−535 but also induce a localized radiation energy deposition by the high-Z Yb, Gd, and Er in UCNPs to favor ROS generation. In vivo

Therefore, the augmentation of inertial cavitation in a tumor region by means of, for example, introducing gas-generating nanomaterials into the US-triggered reaction system can not only facilitate sonodynamic ROS generation for enhanced SDT efficiency (sonochemistry) but also favor localized hyperthermia for improved tumor ablation (accompanied thermodynamics). The integration of sonosensitizer with gas-generating nanomaterials within one single nanosystem is a feasible approach to make use of the inertial cavitation effect for the cooperative enhancements of the two therapeutic modalities. As a typical paradigm, Feng et al. first constructed a pH/US dualresponsive gas generator for simultaneous augmentation of US hyperthermia (in this work referred to as therapeutic inertial cavitation) and SDT (Figure 55).530 Such a nanosystem was

Figure 55. pH/US dual-responsive CO2 generator for inertial cavitation and SDT. (a) TEM image of MCC nanoparticles. (b) Corresponding high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) image of MCC in (a). (c) Optical microscopic images showing the CO2 generation from the HAmodified solid calcium carbonate (SCC-HA) and MCC-HA in PBS at varied pHs with or without US treatment. (d) Schematic illustration for the intracellular therapeutic performance of HMME/MCC-HA. Reprinted with permission from ref 530. Copyright 2017 John Wiley and Sons.

fabricated by loading HMME into mesoporous calcium carbonate (MCC) nanoparticles, followed by the surface modification of HA. The collaborative effect between exogenous US and endogenous mild acidic TME enables MCC degradation and CO2 release, which can not only result in cell necrosis and the blood vessel destruction by localized hyperthermia (physical mechanism) but also augment the sonosensitization of HMME to facilitate ROS generation for oxidative damage on tumor tissues (chemical mechanism). Although SDT is still in its early stage of development, however, their further advances can be inspired from the marked achievements in PDT. For example, (1) numbers of PSs can also respond to US for sonodynamic ROS generation, which can also be explored as sonosensitizers; (2) analogous to light, USs with different frequencies may also lead to varied physicochemical effects (such as sonophoresis, hyperthermia, thrombolysis, etc.), which can be utilized to integrate with SDT for US-triggered synergistic therapy; (3) TME modulation strategy can be utilized to rectify the oxygen deficit of TME, AZ


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Figure 56. Bovine serum albumin (BSA)-coated bismuth oxyiodide (BiOI)@Bi2S3 semiconductor heterojunction nanoparticles (SHNPs) for RT/ PDT/PTT synergistic therapy. TAA, thioacetamide. Reprinted with permission from ref 286. Copyright 2017 John Wiley and Sons.

function of RT for effective mobilization of antitumor immunity. Although radiation alone is rarely sufficient to arouse potent enough immunomodulatory effect for systemic tumor rejection, the integration of radiotherapy with immunotherapy is capable of favoring their cooperative augmentations for enhanced therapeutic efficiency. However, nonsynchronous dosing regimens between RT and immunotherapy are still one of the main challenges in eliciting their optimal synergy. Recently, two pioneering reports have successfully constructed feasible therapeutic platforms to combine RT and immunotherapy for achieving whole-body antitumor effect after local treatment. Lu et al. first took advantage of low-dose X-rayactivated RT and PDT (in this work referred as radiodynamic therapy, RDT) to enhance checkpoint blockade immunotherapy via engineered nanoscale MOFs (Figure 58).299 They fabricated two Hf-based nano MOFs, 5,15-di(p-benzoato)porphyrin-Hf (DBP-Hf) and 5,10,15,20-tetra(p-benzoato)porphyrin-Hf (TBP-Hf), for evaluating their therapeutic potency. The crystalline structures of the two nanosystems guarantee the high densities of PSs, which can be directly excited by low-dose X-ray. The high-Z Hf clusters in the framework of MOFs possess strong X-ray attenuation capabilities, enabling the efficient energy conversion to favor RT via the production of •OH and deep PDT by photosensitization-induced 1O2 generation. The researchers further loaded an indoleamine 2,3-dioxygenase inhibitor (IDOi) into the pore channels of DBP-Hf, for the integration of RT and PDT with immunotherapy. On account of the intrinsic immunomodulatory performances of RT and PDT, the triple therapeutic modalities can be developed in parallel for the

experiments indicated that with the cooperative interaction between PTT and enhanced RT, tumors could be eradicated without visible recurrence within 120 days. Song et al. fabricated core−shell MnSe@Bi2Se3 “nanobullet” to impart synergistic RT/PTT.294 In this hierarchical architecture, Bi2Se3 shell with both strong absorbance of Xray and NIR favors the synergy between RT and PTT for enhanced therapeutic efficacy. Moreover, in another paradigm, Guo et al. fabricated bovine serum albumin (BSA)-coated bismuth oxyiodide (BiOI)@Bi2S3 semiconductor heterojunction nanoparticles (SHNPs) for RT/PDT/PTT synergistic therapy against cancer (Figure 56).286 BiOI acts as both radiosensitizer and PS for concurrent RT and PDT, owing to its high-Z elements of Bi and I for X-ray attenuation and its semiconductor nature favoring the electron−hole pair generation. In addition, the external Bi2S3 coating enables the formation of a heterojunction structure to prevent the electron−hole recombination for efficient ROS generation. More importantly, PTT with intrinsic O2-elevating capability can be further used to mitigate hypoxia and consequently augment RT and PDT, simultaneously. The cooperative augmentation effects among the three therapeutic modalities may present a promising therapeutic approach for tumor therapy in the future. The third strategy is integrating RT with immunotherapy for simultaneous local and remote tumor management. Recent evidence shows that ionizing radiation can be immunomodulatory by altering the microenvironment of the irradiated region (Figure 57).485,536−539 This momentous demonstration has created a wave of interest among oncologists, therapists, and chemists, to take advantage of such a unique immunological BA


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Figure 57. Immunological effect of RT. (a) Step I: Exposure of tumor antigen after RT leads to a potent inflammatory cytokine response that promotes DC maturation and upregulation of appropriate chemokine receptors. (b) Step II: DCs migrate to lymphonodus and express tumor antigens. (c) Step III: Effector T cells home to tumors for therapeutic effect. CRT, calreticulin; HMGB1, high-mobility group box 1; P2RX7, purinogenic receptor; IL, interleukin; NF-κB, nuclear factor-kappa B; C3a−C5a, complement component 3a and 5a receptor; MyD88, Myeloid differentiation primary response gene 88; MHC, major histocompatibility complex. Reprinted with permission from ref 485. Copyright 2017 American Cancer Society. 131

I-CAT but also effectively traps 131I-CAT to circumvent their excessive leakage to normal tissue. The intrinsic enzymatic activity of CAT facilitates the decomposition of overexpressed H2O2 in TME to generate O2, which is capable of relieving hypoxia to favor IRT with a quite low radioisotope dose. More importantly, the introduction of CpG oligonucleotide favors the intratumoral generation of tumor-associated antigens, leading to strong systemic antitumor responses. Such a combined approach offers a remarkable synergistic effect to inhibit remote metastatic tumors, which can also provide long-term immune memory to prevent tumor recurrence. 3.6.4. CDT-Based Synergistic Therapy. The most prominent feature of CDT is the endogenous chemical activation for tumor-specific therapeutic outcome. Although such a TME-responsive therapeutic modality presents unprecedented advantages in cancer treatment, however, the

optimization of therapeutic outcomes. By combining the complementary advantages of local treatment and systemic tumor rejection, this strategy presents a great potential to significantly increase the therapeutic efficacy of metastatic tumors. Moreover, Chao et al. have also combined a local immunostimulatory IRT and systemic CTLA-4 checkpoint blockade to impart potent antitumor responses very recently.540 They integrated CAT and CpG oligonucleotide with sodium alginate to fabricate a multifunctional platform for favoring IRT and immunotherapy simultaneously. In this work, 131I was applied to label CAT and serve as an internal excitation source in IRT. After intratumoral administration of the prepared 131ICat/alginate solution, the physiological Ca2+ will trigger in situ rapid gelation of alginate within tumors, which not only guarantees intratumoral homogeneous distribution of inner BB


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Figure 58. Engineered nano MOFs for synergistic RT/PDT/immunotherapy. (a) Structures of Hf12/Zr12 SBUs and 5,15-di(p-benzoato)porphyrinHf (DBP-Hf), DBP-Zr, and DBA-Hf nano MOFs. (b) Structures of Hf6/Zr6 SBUs and 5,10,15,20-tetra(p-benzoato)porphyrin-Hf (TBP-Hf) and TBP-Zr nano MOFs. (c) Physicochemical mechanisms of low-dose X-ray-activated RT/PDT by nano MOFs. (d) Therapeutic concept and the corresponding immunological mechanisms of IDO inhibitor (IDOi)-loaded nano MOFs. Trp, tryptophan; kyn, kynurenine. Reprinted with permission from ref 299. Copyright 2018 Nature Publishing Group.

phototherapies, as well as the remote and systemic features of CDT, their integration makes them complementary with each other to significantly enhance the antineoplastic effect. We recently prepared antiferromagnetic pyrite as TME-responsive nanoplatform for self-enhanced synergistic PTT/CDT (Figure 59).542 Under the activation of H2O2 in acidic TME, antiferromagnetic pyrite undergoes in situ surface oxidation and consequent Fe valence elevation, accompanied by significant enhancement of catalytic performance, during which its identification transforms from initial noncatalytic substance to highly efficient Fenton nanocatalyst to favor the decomposition of intratumoral H2O2 and the generation of • OH for TME-specific CDT. Moreover, the localized hyperthermia by photothermal process can also accelerate the Fenton reaction, thus augmenting CDT for a synergistic therapeutic outcome. Liu et al. also fabricated biocompatible copper ferrite nanospheres (CFNs) as an “all in one” platform for CDT/ PDT/PTT synergistic therapy (Figure 60).391 Cytotoxic •OH and O2•− will be produced as a consequence of photo-

totally spontaneous reaction in CDT may lead to nondeterminacy in ultimate therapeutic effect on account of the complex and dynamic features of TME. Thus, exogenous intervention is desired to assist temporospatial control of such a spontaneous therapeutic process for improved therapeutic outcome. In the previous section, we have elucidated that exogenous physical irradiations, such as light and US, can be used to control/regulate a Fenton-based catalytic ROSgenerating process; here, we concentrate on the integration of CDT with physical-irradiation-triggered therapeutic modalities, such as PTT and PDT, which provide controllable and complementary effects for the optimization of the treatment outcome. As discussed above, light of certain wavelengths may promote Fenton reactions for enhanced •OH-generating efficiency.541 Thus, the introduction of phototherapies (PTT/ PDT) is capable of augmenting the therapeutic performance of CDT, resulting in a superadditive effect. More importantly, considering the localized and focused characteristics of BC


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IONP-based nanosystems for superadditive therapeutic effect. It is highly expected that more progress will be made in the future by taking advantage of the dual-functions of IONP (catalytic activity and immunoregulatory effect) for the cooperative augmentation of anticancer outcome. Synergistic therapy harbors the collective merits of and the synergetic effects among individual therapeutic modalities to yield much stronger therapeutic effects than their linear combinations. In the past decade, extensive efforts have been invested in the fabrication of synergistic therapeutic platforms to integrate different ROS-generating/responsive therapeutic modalities (PDT, SDT, RT, CDT, CDR), or with other therapeutic modalities (PTT, immunotherapy, gene therapy, etc.) for more potent antineoplastic performances based on their varied but intertwined therapeutic mechanisms (Table 6). In view of the increasingly severe status of cancer across the world, we are obliged to acquire a better understanding of the intrinsic characteristics of each ROS-based therapeutic modality (Table 7) and determine to what extent and in what ways the combined therapeutic approaches are significantly advantageous over discrete steps of monotherapies. At present, advances in ROS-based cancer therapeutics are still confined in academic settings.544 However, we believe that the persistent developments of ROS science and oncology will further benefit the optimization of antitumor performance of nanomedicines to win the campaign against cancer.

Figure 59. Antiferromagnetic pyrite as TME-responsive nanoplatform for self-enhanced CDT/PTT synergistic therapy. Reprinted with permission from ref 542. Copyright 2017 John Wiley and Sons.

generation of electron−hole pairs in CFNs (type I PDT). In addition, the coupling between two redox pairs (Fe2+/Fe3+ and Cu+/Cu2+) in CFNs accelerates •OH generation through Fenton and Fenton-like reactions, which can be further enhanced by localized hyperthermia under 650 nm laser illumination. The cooperative enhancements of CDT, PDT, and PTT by such a designed nanosystem provide us with more advanced tools for the amplification of the anticancer therapeutic effect. A recent breakthrough in immunology indicates that IONPs are capable of inhibiting tumor growth by promoting proinflammatory macrophage polarization in tumor tissues.543 In this work, researchers suggested that IONPs could be applied as an “off label” to protect liver from metastatic seeds attack and potentiate immunotherapies. According to the intrinsic Fentonlike activity of IONPs in acidic TME, this report inspires researchers to integrate CDT with immunotherapy by utilizing

4. ROS-RELATED NANOTHERAPY FOR OTHER PATHOLOGICAL ABNORMALITIES ROS biology is a highly complex subject. The overproduction of ROS in cells may lead to numbers of downstream pathological dysfunctions besides cancer, such as neurodegenerative disorders,545−551 inflammation,552−556 vascular diseases,557−560 etc. (pathological effects). However, these overexpressed ROS can also help the host to fight against microorganisms and present antimicrobial potential for prevention of infectious diseases (therapeutic effects).102,561−566

Figure 60. Biocompatible copper ferrite nanospheres (CFNs) as “all in one” platform for CDT/PDT/PTT synergistic therapy. (a) Synthetic process and therapeutic mechanism of CFNs. (b) Relative absorption of DPBF at 410 nm in the presence of CFNs with or without H2O2 addition and light irradiation. (c) O2 generation in the presence of CFNs with or without the addition of H2O2. (d) Photothermal heating curves of CFNs with different concentrations under the irradiation of 808 nm laser (power density: 1.3 W cm−2). (e) Infrared thermal images of aqueous solutions with varied concentrations of CFNs under the irradiation of 808 nm laser (power density: 1.3 W cm−2). Reprinted with permission from ref 391. Copyright 2018 American Chemical Society. BD


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Table 6. Summary of the Representative ROS-Based Platforms for Synergistic Cancer Therapy matrixes

functional component

exogenous or endogenous stimuli

therapeutic modalities

Ce-UCNP

CeO2, Yb3+, Tm3+, Dox

NIR, H2O2, H+

PDT, chemotherapy

HSA, MnO2

Ce6, cis-platinum prodrug scintillator, ZnO

661 nm laser, H2O2, H+

PDT, chemotherapy

X-ray

PDT, RT

PDT, RT

SZNP

MnO2

UCNP

UCNP

Ce6, R837

NIR, X-ray, H +, H 2 O 2 NIR

PMIL

BPD, XL184

NIR

PDT, immunotherapy PDT, CDR

Liposome

IR780

NIR

PDT, PTT

BP

BP, Dox

NIR, 660 nm laser

PDT, PTT, chemotherapy

Pluronic F68 Pluronic F68 HMON

HP, Dox

US

HP, Dox

US

PpIX, Dox

US, GSH

MCC

HMME

US, H+

TaOx

SN38

X-ray

UCNP@ SiO2 UCNP@ SiO2 MnSe

cisplatin

X-ray

CuS

X-ray, NIR

SDT, chemotherapy SDT, chemotherapy SDT, chemotherapy SDT, US hyperthermia RT, chemotherapy RT, chemotherapy RT, PTT

Bi2Se3

X-ray, NIR

RT, PTT

Bi2Se3

Bi2Se3

X-ray, NIR

SHNP

BiOI, Bi2S3

X-ray, NIR

RT, PTT, radioprotection RT, PDT, PTT

MOF

X-ray

FeS2

Hf cluster, IDOi FexO

CFN

CFN

NIR, 650 nm laser, H2O2, H+

NIR, H2O2

RT, PDT, immunotherapy CDT, PTT

CDT, PDT, PTT

working mechanisms

refs

Catalytic decomposition of endogenous H2O2 in tumor to generate sufficient O2 and enhance PDT; conversion of NIR light to UV emission to trigger ROS generation; pH-responsive Dox release in acid tumor site MnO2 facilitates O2 generation to enhance PDT process and favors the disintegration of nanoparticles for improved intratumoral interstitial diffusion and optimized chemotherapy

525

X-ray induces RT; the downconverted UV fluorescence emitted from scintillator core under X-ray irradiation enables electron−hole pair formation in ZnO to facilitate •OH generation for type I PDT Reaction between MnO2 nanosheets and acidic H2O2 in TME enables massive O2 generation to modulate hypoxic TME and enhance PDT and RT concurrently NIR-triggered PDT by UCNP-Ce6-R837 enables the generation of ROS for PDT; CTLA-4 checkpoint blockade assists antitumor immune responses Exogenous NIR light activates PMILs to impart ROS generation and sustained release of XL184, leading to tumor cell apoptosis and necrosis, as well as multikinase inhibition IR780 in perfluorooctyl bromide liposomes can act as both PS and photothermal agent to favor PDT and PTT under one single NIR excitation Unique energy band structure of BP and its broad absorptions across the entire visible light region favors desired ROS generation and photothermal conversion; large specific surface area for drug delivery Synergistic effects between ROS generation and Dox release to inhibit HCC growth and progression through multiple mechanisms Synergistic effects between ROS generation and Dox release to inhibit HCC growth and progression through multiple mechanisms US-triggered ROS generation for SDT; GSH-responsive breaking up of disulfide bonds in the framework of HMONs for biodegradation and Dox release CO2 release from HMME/MCC-HA under US treatment results in cavitation-mediated, hyperthermia-induced cell necrosis, as well as the augmentation of SDT process TaOx attenuates X-ray to enhance RT; SN38 can induce cycle arrest of tumor cells into radiosensitive phases for RT enhancement Cisplatin acts as both anticancer drug and radiosensitizer; hollow cavity and porous shell of UCNP@SiO2 guarantee high loading efficiency of cisplatin High-Z rare earth elements of Yb-based UCNP enhance RT; CuS satellites are responsible for converting the NIR into heat for PTT NIR-triggered temperature elevation during PTT favors the reoxygenation of hypoxic tumor to overcome hypoxia-associated radioresistance for enhancing RT NIR absorption and X-ray attenuation of Bi2Se3 favor PTT and RT; selenium release from the nanoparticle reduces the side-effect of radiation BiOI acts as both radiosensitizer and PS for RT and PDT; Bi2S3 with high photothermal conversion property favors PTT High-Z number Hf with strong X-ray attenuation enables efficient energy conversion for RT and deep PDT; the loaded IDOi enhances checkpoint blockade immunotherapy TME-mediated surface oxidation and valence elevation of Fe species in FeS2 elevates the catalytic efficiency; the photothermal effect of FeS2 accelerates Fenton-like reaction for synergetic PTT/ CDT Coupling between two redox pairs (Fe2+/Fe3+ and Cu+/Cu2+) of CFNs promotes •OH generation for enhanced CDT; photothermal effect and photosensitization of CFN enables synergistic CDT/PDT/PTT

486

524

523 515 518 501 484

528 527 249 530 295 303 302 294 293 286 299 542

391

unique roles that ROS-based nanomedicines played in governing ultimate therapeutic outcomes.

Such a biological pleiotropy of ROS suggests that we may be able to conceive proper redox-regulating strategies (promote ROS depletion or foster ROS production) to cope with specific circumstances for therapeutic applications.567 In the above sections, we have elucidated diverse ROSupregulating strategies for antineoplastic therapy assisted by redox-active nanoplatforms and here, an overview on the nanomedicine-guided redox-regulating therapeutic strategies against other pathological abnormalities will be provided, from ROS-scavenging/responsive nanoplatforms for the treatment of brain diseases (e.g., neurodegenerative diseases, ischemic stroke), inflammatory diseases (e.g., periodontal disease, intestinal inflammation), and cardiovascular diseases (e.g., myocardial infarction) to subsequent ROS-generating nanosystems with varied functional mechanisms for antibacterial applications. Moreover, the underlying ROS-related pathology and iatreusiology in these pathological dysfunctions will also be discussed, to offer readers a clear picture on the

4.1. Brain Diseases

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have been becoming a focus in neuropathology due to their increasing morbidity and mortality.568 Although still controversial, increasing numbers of sound research have evidenced that excessive generation of ROS contributes to the neurodegeneration.569−571 For example, elevated ROS levels would lead to the dysregulation of intracellular Ca2+ signaling that induces an apoptotic cascade (such as excitotoxic response).572 The biogenesis of these excessive ROS can be attributed to the endogenous transitionmetal dyshomeostasis in brain as the consequence of normal aging progression (Figure 61).573−575 The upregulated levels of redox-active metals, such as Cu and Fe, could lead to BE


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Table 7. Summary of the Characteristics of ROS-Based Cancer Therapeutic Modalities therapeutic modalities

general excitation source

general working principles

advantages

disadvantages

strategies for further enhancement

PDT

UV−vis light

light activates PS to transfer its excited-state energy to ambient oxygen for ROS generation

localized treatment; minimal invasiveness; immunological effect

oxygen dependence; limited tissue penetration depth; concurrent heat generation; self-catalyzation of PS

SDT

US

cavitation effect causes sonoluminescence or pyrolysis of sonosensitizer to favor ROS production

deep tissue penetration; localized treatment; mitigated side effect

oxygen dependence; rapid US wave attenuation; concurrent heat generation; self-catalyzation of sonosensitizers

RT

X-ray

X-ray-induced various physical processes, such as photoelectric effect, Compton scattering, Auger effect, etc., to enable ROS generation

deep tissue penetration; localized treatment; immunological effect

oxygen dependence; radiation resistance; serious systemic side effect

CDT

chemicals in TME

endogenous biochemical stimuli initiate specific chemical reactions [e.g., Fenton(-like) reactions] to facilitate ROS generation within tumor

TME-selectivity and specificity; free from tissue penetration limitation

H2O2 dependence; less manageable reaction process

CDR

ROS

ROS-triggered compositional or structural variation of nanomedicines to facilitate the release of guest molecules

TME-selectivity and specificity; free from tissue penetration limitation

less manageable reaction process

1. creating novel PSs such as type I PSs; 2. utilizing different light excitation sources such as NIR, X-ray, CR, etc.; 3. modulating TME to relieve hypoxia 1. fabricating novel sonosensitizers with enhanced ROS-generating capability; 2. modulating TME to relieve hypoxia; 3. enhancing cavitation effect 1. designing novel radiosensitizers with elevated X-ray attenuation ability; 2. modulating TME to relieve hypoxia; 3. mitigating radiation-induced side effects for radioprotection 1. preparing more efficient nanocatalysts; 2. developing H2O2-elevating strategies such as the addition of GOD or CaO2; 3. applying external excitation sources to control the ROS-generating process 1. establishing “smarter” multifunctional CDR system; 2. improving ROS sensitivity of nanocarriers; 3. applying external excitation sources to control the CDR process

Figure 61. Schematic illustration for the underlying chemical principles of neurodegenerative diseases. Reprinted with permission from ref 573. Copyright 2018 American Chemical Society.

BF


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Figure 62. H2O2-responsive magnetic composite nanoplatform for AD treatment. (a) In vivo working mechanisms of Congo red and Rutin coloaded magnetic nanoparticles (Congo red/Rutin-MNPs). (b) Chemical structures of as-decorated organic component and the synthetic procedure of Congo red/Rutin-MNPs. Reprinted with permission from ref 600. Copyright 2015 John Wiley and Sons.

zymes) to scavenge excessive ROS in brain for antioxidative therapy; and (3) constructing feasible nanoplatforms as metal chelators to modulate the upstream metal−protein interactions (such as Cu with Aβ) for inhibiting ROS overproduction. In the following sections, we will discuss the recent advances in the elaborate design of advanced nanomedicines for favoring neuroprotective therapy. 4.1.1. ROS-Responsive Nanoplatforms To Facilitate Neuroprotective Drug Release. Analogous to cancer CDR, neuroprotective therapy can also take advantage of pathological ROS (especially H2O2) as endogenous biochemical stimuli to activate redox-responsive nanomedicines for site-specific drug release. However, on account of the intrinsic biological characteristics of brain that are totally different from tumor, the basic design rationales for the fabrication of neuroprotective nanosystems are supposed to be reconsidered: (1) As the exclusive biological barrier, the BBB can protect the brain from the attack of extrinsic potentially harmful compounds and therefore, unfortunately, prevent intracephalic accumulation of as-administrated nanoparticles, largely compromising their downstream therapeutic effect.599 Thus, rational design of nanoformulations by means of, for example, tailoring them with ultrasmall particle size, is the prerequisite to confer enhanced possibility to cross such a biological barrier for an improved therapeutic efficiency. (2) Nanoparticles with unique size effect can target the tumor region passively and spontaneously by endogenetic EPR effect in tumor microvascular systems. However, such an innate biophysical mechanism does not exist in brain due to their distinct structural differences from each other. Therefore, targeting modification on the surface of nanomedicines is also indispensable for guaranteeing their effective intracephalic accumulation and subsequent antioxidative performance. As a typical paradigm, Hu et al. constructed an H2O2responsive magnetic composite nanoplatform for AD treatment, by decorating Congo red and Rutin on the surface of Fe3O4 nanoparticles (Congo red/Rutin-MNPs, Figure 62).600 Assisted by the intrinsic biological feature that neuroinflammation during AD can compromise the BBB and favor extrinsic agent penetration,601 such a well-designed composite therapeutic nanosystem with ultrasmall particle size is able to

hypermetalation of proteins, increasing the probability of undesired ROS generation.576−578 The ROS-involved pathogenesis for specific neurodegenerative disorders is diversified.11 In AD, the major source of intracephalic oxidative stress is from the metabolism of amyloid-β peptide (Aβ), which possesses histidine residues to favor its coordination with transition metal ions such as Cu2+ or Fe3+.579−582 In this process, the valences of transition metals will be reduced to catalyze the generation of H2O2 from dissolved O2 molecules.571 Specifically, the reduction potential of Cu2+ to Cu+ in the presence of Aβ42 is highly positive,11 conferring a high reactivity for such a reduction process. Moreover, the generated H2O2 can be further decomposed into highly toxic •OH by Fenton-like reactions in the presence of Cu+, resulting in accentuated neurotoxicity.11,583,584 Comparatively, in PD, the major protein component related to pathogenicity is α-synuclein,585 which plays a vital role in modulating the intracellular equilibrium of dopamine.52 As an essential neurotransmitter, dopamine can also serve as a good metal chelator to coordinate and reduce Cu2+ and Fe3+,11 resulting in the formation of neuromelanin and •OH.586−588 Additionally, neuromelanin will also coordinate Fe and further produce cytotoxic ROS.589,590 Such a dopamine-induced ROS generation can be regulated by α-synuclein,591,592 and mutations in this protein will lead to the elevated intracellular oxidative stress and downstream neural dysfunctions.593,594 In addition to neurodegenerative diseases, ischemic stroke is also one of the leading brain diseases in which overexpressed ROS are responsible for causing neuron injury.595 It has been demonstrated that, after reperfusion, ROS will be upregulated in the ischemic site, leading to the oxidative damage on neurocytes for cell apoptosis.596−598 Based on ever-deeper elucidations on ROS-related pathogeneses of neurodegenerative diseases and ischemic stroke, in recent years, large numbers of ROS-based nanotherapeutic strategies have been developed to cope with these neural dysfunctions for neuroprotective therapy. In general, these strategies can be categorized into three typical methodologies: (1) designing ROS-responsive nanomedicines for controlled release of neuroprotective drugs specifically at pathological sites; (2) fabricating catalytic nanomaterials (such as inorganic nanoBG


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Figure 63. CeO2 nanoparticles with SOD-mimetic and CAT-mimetic activities for neuroprotective therapy. (a) CeO2 nanoparticles to protect against oxidative damage after ischemic stroke. (a1) TEM image (left), HRTEM image (middle), and the SAED pattern (right) of CeO2 nanoparticles. Scale bars, 100 nm, 5 nm and 5 nm−1, respectively. (a2) Representative slices of brain tissues in different groups to investigate the therapeutic effect of CeO2. (a3) 3D reconstruction for the fluorescence signals of CeO2 nanoparticles by computerized visual augmentation. Significant increase of signal intensity can be visualized in the peri-infarct area. Reprinted with permission from ref 607. Copyright 2012 John Wiley and Sons. (b) Mitochondria-targeting CeO2 nanoparticles as efficient antioxidants for the catalytic treatment of AD. (b1) Biochemical mechanisms of mitochondria-targeting CeO2 nanoparticles. (b2) Confocal fluorescence images of SH-SY5Y cells for evaluating ROS-scavenging ability. Reprinted with permission from ref 609. Copyright 2016 American Chemical Society. (c) Hyperphosphorylated tau-targeted multifunctional nanosystems for the combinational treatment of AD. (c1) Functional motifs on the surface of as-designed composite nanoplatforms, including CeO2 nanoparticles, IONPs, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-T807, and MB. (c2) Synthetic procedure of hyperphosphorylated tau-targeted multifunctional nanocomposites (CeNC/IONC/MSN-T807-MB). (c3) Chemical mechanism of CeNC/IONC/MSN-T807-MB-based synergistic nanotherapy. PET, positron emission tomography; MRI, magnetic resonance imaging. Reprinted with permission from ref 613. Copyright 2018 American Chemical Society.

functionalized with boronic ester and an RBC membrane shell engineered with stroke homing peptide, presenting prolonged circulation lifetime and enhanced targeting efficiency. After internalization by ischemic neurons, the intracellular H2O2 will activate boronic ester to facilitate the disintegration of nanocarrier and the release of inner neuroprotective agent, lys-leu-ser-ser-ileglu-ser-asp-val (NR2B9C), which can selectively disrupt the N-methyl-D-aspartate receptors (NMDARs) with the postsynaptic density protein (PSD-95) to prevent the overproduction of toxic NO. This pioneering work employs advanced cell membrane coating nanotechnology to confer

cross the BBB and exert its therapeutic effect subsequently. In addition, the as-loaded Congo red is also capable of binding with Aβ plaques specifically to endow the nanoformulation with improved targeting effect for enhanced intracephalic accumulation. Specifically, the boronate ester bond between the vicinal diols of Rutin and phenylboronic acid presents H2O2responsiveness for controlled release of therapeutic Rutin, an antioxidative glycone of quercetin, contributing to the maintenance of redox homeostasis in the pathological region. In another representative work, Lv et al. have also constructed a bioengineered H2O2-responsive nanocarrier for stroke-specific drug release.602 It is composed of a dextran core BH


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improved biological behaviors,603 further promoting the application of nanomedicines in neuroprotective therapy. 4.1.2. Catalytic Depletion of Excess ROS by Enzymatic Reactions. In addition to the aforementioned strategy, direct delivery of catalytic ROS-scavenging nanosystems is also a feasible approach to downregulate intracephalic oxidative stress for a detoxification effect. Recent advances in enzymology have provided effective tools to scavenge intracephalic ROS, and specifically, a number of inorganic nanozymes with intrinsic antioxidative capacities have also been developed as therapeutic agents for neuroprotection, among which CeO2 is the most prominent one.604,605 On account of the SOD and CAT-like activities of CeO2 nanoparticles that confer intrinsic sequential ROS-scavenging performances (i.e., from O2•− to H2O2 to H2O), such an active nanomaterial is promising to be applied for antioxidative therapy of brain diseases. An early phenomenological study in 2006 by Schubert et al. first reported the neuroprotective activity of CeO2 in HT22 cells.606 In a significant work in 2012, Kim et al. further demonstrated the protective effects of PEGylated CeO2 nanoparticles against ischemic stroke in living animals (Figure 63a).607 They pointed out that brain ischemia could lead to the breakdown of the BBB, favoring the penetration of CeO2 nanoparticles into the brain. Inspired by this work, we recently fabricated a CeO2-based composite nanosystem for improved therapeutic efficiency, by engineering PEG, angiopep-2, and edaravone on the surface of CeO2 nanoparticles.608 The loaded edaravone provides a complementary antioxidative effect to that of CeO2 nanoparticles for downregulating the oxidative stress in both the BBB and the intracephalic pathological region, while angiopep-2 serves as a targeting ligand that can bind to the LRP overexpressed on cells of the BBB, facilitating active BBB crossing of the as-fabricated nanosystem, finally resulting in high accumulation in intracerebral lesions for ischemic stroke treatment. The investigation of CeO2 nanoparticles in the treatment of ischemic stroke also benefits their applications in coping with other neural abnormalities, such as AD. Given mitochondrial dysfunction is a key pathologic factor in AD that initiates excessive ROS generation and leads to neuronal cell death, Kwon et al. designed a CeO2-based nanoplatform with mitochondria-targeting capability for mitigating mitochondrial oxidative stress in AD treatment (Figure 63b).609 They engineered CeO2 nanoparticles with triphenylphosphonium (TPP), a lipophilic cation that can target mitochondria via electrostatic adsorption. Enhanced mitochondrial localization and neuronal death suppression were evidenced in a 5XFAD transgenic AD mouse model, demonstrating the feasibility of such a subcellular targeting strategy. Recent studies have shown that the tau pathway is closely associated with development of AD, which provides a potential therapeutic target.610−612 In light of this, Chen et al. prepared tau-targeted multifunctional nanocomposite for combinational therapy of AD (Figure 63c).613 They integrated CeO2 nanoparticles, IONPs, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-T807, and MB on the surface of MSNs, to endow such an “all in one” composite nanoplatform (CeNC/ IONC/MSN-T807-MB) with remarkable versatility for improved AD nanotherapy. T807 possesses a high binding affinity to hyperphosphorylated tau, favoring the active targeting, while the intrinsic sequential catalytic ROS-scavenging capability of CeO2 facilitates the downregulation of mitochondrial ROS level. Moreover, the simultaneous MB release enables the

inhibition of hyperphosphorylated tau aggregation, exerting a synergistic therapeutic effect. A recent report showed that CeO2 nanoparticles could modulate the phenotypic polarization of microglia for neuroprotection,614 further evidencing that such a nanozyme is capable of exerting significant therapeutic efficacy in the treatment of brain diseases. In addition to CeO2, other inorganic nanozymes with intrinsic antioxidative activity have also been explored as therapeutic agents for neuroprotection. Zhang et al. first demonstrated that Fe3O4 nanoparticles with CAT-like activity in intracerebral microenvironment are capable of scavenging excessive H2O2 to antagonize oxidative stress and ameliorate neurodegeneration in drosophila AD model.615 On account of the peroxidase-like activity of Fe3O4 in acidic TME that facilitates •OH generation for cancer CDT, such a discovery may enable the combination of glioblastoma treatment and neuroprotection based on the spatiotemporal pH variation of brain and downstream different catalytic activities of Fe3O4. In addition, Ren et al. reported that graphene oxide (GO) quantum dots could reduce oxidative stress and inhibit neurotoxicity through CAT-like activity.616 Increased Nissl bodies were visualized in the brains of larval zebrafishes pretreated with GO quantum dots, confirming the potent antioxidative activity of GO in mitigating neurotoxicity. Organic nanosystems have also been explored as neuroprotective agents in parallel owing to their desirable biocompatibility and biodegradability compared with inorganic nanomaterials. An early work in 2008 by Reddy et al. reported that SOD-loaded PLGA nanoparticles can protect cultured human neurons from oxidative stress. 617 The PLGA encapsulation not only protects inner SOD from exogenic turbulence during intravascular delivery but also favors the neuronal uptake for enhanced therapeutic efficacy. This work inspired researchers to take advantage of recent advances in the smart design of multifunctional nanocarriers, to enable efficient delivery of natural enzymes for enhanced neuroprotective effect. Specifically, exosomes, which are small membrane vesicles secreted by most cells, have recently been developed as robust natural nanocarriers to deliver antioxidative enzymes or their precursors (e.g., mRNA) to recipient cells for neuroprotective therapy, based on their unique endogenous functionalities such as target-homing specificity, immunosurveillance, and BBB crossing capability.618−625 Recently, Kojima et al. engineered HEK-293T cells with genetic devices to facilitate the secretion of exosomes with biopharmaceuticalencoding mRNA that can express CAT in Neuro2A cells for PD treatment (Figure 64).626 These as-secreted multifunctional exosomes serve as versatile nanoplatforms to favor targeted exosomal mRNA delivery and subsequent CAT expression, presenting a promising strategy for efficient neuroprotection. The above organic nanosystems take advantage of artificial/ natural nanocarriers to endow inner functional molecules (i.e., enzymes and mRNA precursors) with improved biostability and BBB penetrability. Based on the nanosynthetic chemistry, natural biopolymers can also be directly tailored as catalytic nanoparticles for neuroprotective therapy. Liu et al. recently prepared melanin nanoparticles as robust antioxidants to protect ischemic brain from ROS-induced damage.627 In this work, they demonstrated that such a pristine catalytic nanosystem presents broad antioxidative activities against multiple ROS including O2•−, H2O2, and •OH, displaying superiority over most natural antioxidant enzymes that are only capable of scavenging one specific type of ROS. In a rat model BI


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homeostasis, targeting such interactions by delivering metal chelators to compete with target protein for metal ion capture will be applicable to inhibit the deleterious effects of aberrant metal concentrations. This strategy, which takes advantage of exogenous chelating agents to disrupt the abnormal metal− protein interaction for normalizing metal distribution, is capable of inhibiting the toxic cycle (i.e., ROS generation) for significantly improved therapeutic outcome. To design a potent metal chelator, the material should be able to efficiently capture the active metal dispersed in the intracerebral microenvironment to form a nontoxic metal complex. Moreover, BBB penetrability is also the basic criterion for the success of metal chelators to cross the well-formed tight junctions and exert their ultimate therapeutic effects. Numbers of nanomaterials have been evidenced to show copper-chelating capability for neuroprotection.11 On account of the dominant role of copper dyshomeostasis in the pathogenesis of AD, such a “copper chelation” strategy presents a significant therapeutic effect in the regulation of oxidative stress.628 As a typical paradigm, Gao et al. first fabricated POMbased multifunctional nanozyme with protease activity, SODlike functionality, and Cu2+ chelation capability for synergistic AD treatment.629 In this study, POM, octa-peptide, and LPFFD peptide were decorated on Au nanoparticles to fabricate such a composite catalytic nanosystem based on the conventional Au− S chemistry. Au nanoparticles not only facilitate electron transfer between POM and the hepta-peptides but also serve as robust nanocarriers for BBB penetration. POM with WellsDawson structure (POMD) inhibits the in vitro aggregation of Aβ, presenting protease-like activities, while LPFFD peptide targets Aβ specifically for improving intracerebral accumulation. Moreover, the as-decorated hepta-peptides (stemming from

Figure 64. Engineered exosomes for intercellular CAT mRNA delivery and enzymatic ROS depletion. Schematic illustration for the intercellular crosstalk between Neuro2A cells and injected exosome producer cells for PD treatment. Reprinted with permission from ref 626. Copyright 2018 Nature Publishing Group.

of ischemic stroke, they further demonstrated that the administration of PEGylated melanin nanoparticles could lead to a significant decrease of infarct area, evidencing the feasibility of such organic nanoparticles as efficient therapeutic antioxidants for neuroprotection. 4.1.3. “Copper Chelation” Strategy To Assist ROS Decomposition. Although the construction of ROS-responsive/scavenging nanosystems has made preliminary achievements in brain therapy, however, both the therapeutic options do not target the underlying causes of elevated ROS level, but the consequences.11 If the medication is stopped, patients may still suffer from the risk of relapse. Thus, a treatment strategy for directly coping with the upstream origin of ROS will be more effective in relieving the oxidative stress.11 Given metal− protein interactions are the dominating causes of oxidative stress, which aggravate the breakdown of intracerebral redox

Figure 65. 2D BP nanosheets as an efficient nanodrug to capture excessive Cu2+ for neurodegenerative disorder therapy. (a) Schematic illustration for the therapeutic mechanism of BP nanosheets. (b, c) TEM images of BP nanosheets before (b) and after (c) Cu chelation. Scale bars, 200 nm. (d) Elemental mappings of P and Cu for pristine BP nanosheets and BP-Cu complex. Scale bars, 50 nm. (e) XPS spectra of pristine BP nanosheets and BP-Cu complex. (f) Binding ability of BP nanosheets to various metal ions in the figure, demonstrating the high specificity of BP for Cu2+ chelation. (g) Inhibition of Cu2+-induced H2O2 generation by BP nanosheets. (h) Cell viability assay in different groups to evaluate the therapeutic efficacy of BP nanosheets. Reprinted with permission from ref 635. Copyright 2017 John Wiley and Sons. BJ


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octa-peptides) not only present excellent SOD-like activity for the depletion of excessive ROS but also capture excessive Cu2+ to prevent downstream Fenton-like reactions. More importantly, such SOD-like activity can be further enhanced after Cu2+ chelation, further augmenting ROS depletion. The elaborately engineered multifunctional nanozyme presents comprehensive and superadditive therapeutic functions, paving a new way for efficient AD treatment. 2D nanomaterials have attracted broad attention in the past several years owing to their unique physicochemical properties.630−634 In a recent study, Chen et al. applied 2D BP nanosheets as efficient copper chelators to facilitate the generation of BP-Cu complex for neuroprotective therapy (Figure 65).635 Based on thermodynamic calculation, the change of Gibbs free energy (ΔG) during the reaction between P and Cu2+ is highly negative, much lower than that of the reaction between P and other metal ions (Ca2+, Mg2+, Fe2+, Fe3+, and Zn2+), indicating the high specificity of copper chelation by BP nanosheets. In vitro experiment indicated that • OH production would be inhibited after the addition of BP, further evidencing its desirable chelating performance. Furthermore, the local temperature elevation by photothermal conversion of BP nanosheets under NIR irradiation is also beneficial for improving their BBB permeability. Therefore, BP nanosheets display potent therapeutic capability to regulate copper dyshomeostasis and inhibit downstream ROS overproduction, and it is expected that more efficient nanosystems will be developed as multifunctional metal chelators in the future to treat neurodegenerative disorders.

Figure 66. Interplay of ROS and inflammation in specialized cells, which determines many downstream pathological dysfunctions. UPR, unfolded-protein response. Reprinted with permission from ref 637. Copyright 2008 Nature Publishing Group.

anti-inflammatory drug release. Moreover, exogenous physical irradiations have also been explored as supplementary tools to regulate such a ROS-involved therapeutic process. In this section, we will concentrate on three therapeutic protocols and discuss the underlying material chemistries of nanomedicines that underpin their therapeutic performances. 4.2.1. ROS Depletion by Organic/Inorganic Antioxidants. Traditional molecular antioxidants for inflammation treatment are, unfortunately, largely problematic due to their nonspecific biodistribution, rapid renal excretion, poor tissue permeability, and low retention at pathological sites.642 Fortunately, recent development in nanotechnology has greatly benefited the fabrication of ROS-scavenging nanosystems for anti-inflammatory therapy. On account of the diversity and complexity of inflammation-associated diseases, these nanosystems can be elaborately tailored based on the specific biological scenarios (location, physicochemical cues, immunologic environment, etc.) to improve their biostability in transport pathways and accumulation in pathological lesions, thus fully exerting their therapeutic performances. For example, oral administration for the treatment of inflammatory bowel disease (IBD) typically requires nanomedicines with high enough stability during gastrointestinal transport. As a typical paradigm, Zhang et al. constructed a SOD/CAT mimetic nanoplatform for the treatment of IBD, by integrating SOD-mimetic Tempol (Tpl) and CAT-mimetic βcyclodextrin into one single nanosystem.643 Due to the intrinsic passive targeting capability of nanoparticles toward inflamed intestinal tissues, where increased epithelial permeability greatly favors their accumulation, such a developed nanomedicine exhibited high bioavailability, benefiting the subsequent intestinal ROS depletion for colitis treatment. In a recent work, Li et al. fabricated a broad-spectrum ROS-scavenging nanosystem for inflammation prevention, by sequentially conjugating two functional moieties, Tpl and phenylboronic acid pinacol ester (PBAP), onto a β-cyclodextrin scaffold.642 Such a composite nanosystem features tunable size and

4.2. Inflammatory Diseases

Inflammation is a natural response of the immune system to injury and infection, which can lead to the release of inflammatory substances (cytokines, radicals, hormones, and other small molecules) and thus favoring the protection of the human body against these pathological aberrations.636 However, there is epidemiological and clinical evidence indicating that excessive inflammation is detrimental and associated with a number of pathological dysfunctions, such as hepatitis, rheumatoid arthritis, diabetes, as well as neurodegenerative and cardiovascular diseases.637−639 It has now been elucidated that, aberrant ROS generation is one of the crucial mediators in the pathogenesis of inflammation (Figure 66).637 During the process of oxidative protein folding in ER, the formation of a disulfide-bond requires the use of molecular oxygen as the terminal electron acceptor, which leads to the production of H2O2.640 Moreover, additional oxidative stress can also be initiated by the substantial consumption of reductive GSH in this process.637,641 These generated ROS favor Ca2+ release from ER to cytosol and the inner matrix of the mitochondria, where Ca2+ disrupts the Mito-ETC, leading to a second production of ROS. Furthermore, these ROS will further promote Ca2+ release from the ER, resulting in continuous cycles of oxidative stress elevation that finally reaches the toxic threshold, and consequently various inflammation-associated pathological abnormalities. Anti-inflammatory therapeutics have been extensively developed for decades, among which targeting excessive ROS for interrupting aberrant inflammatory response has been considered as a feasible strategy for inflammation inhibition. A considerable number of nanomedicines have been elaborately engineered to confer ROS-scavenging capability for direct detoxification or to impart ROS-responsiveness for site-specific BK


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Figure 67. Organic/inorganic antioxidative nanoplatforms for anti-inflammatory applications. (a) Organic polydopamine nanoparticles as ROS scavengers for the treatment of periodontal disease. (a1) Synthesis and anti-inflammatory application of polydopamine nanoparticles. (a2, a3) Scavenging efficiencies of •OH (a2) and O2•− (a3) in the presence of polydopamine nanoparticles. PDA, polydopamine. Reprinted with permission from ref 645. Copyright 2018 American Chemical Society. (b) Inorganic CeO2−zirconia (CZ) composite nanozymes with enhanced antioxidative activity for sepsis treatment. (b1) Chemical mechanism and biological effect of CeO2 and CZ nanoparticles. LPS, lipopolysaccharide; CLP, cecal ligation and puncture. (b2) XPS spectra of CeO2 nanoparticles and CZ nanoparticles, where Ce3+ peaks are highlighted in yellow bands. (b3) Temperature-programmed reduction (TPR) analysis to investigate the effect of Zr4+ incorporation on the reduction activity of CeO2 nanoparticles. Reprinted with permission from ref 647. Copyright 2017 John Wiley and Sons.

Figure 68. ROS-responsive gas-generating carrier for controlled anti-inflammatory drug release and localized inflammation inhibition. (a) Design rationale and therapeutic concept of the hollow microsphere (HM) carrier. OA, osteoarthritis. (b) US imaging showing the generation of CO2 bubbles responsive to acidic H2O2. RRHMs: HMs containing DEX-P, SBC, ethanol, and FeCl2; AHMs: HMs containing DEX-P, ethanol, and FeCl2; SHMs: HMs containing DEX-P and SBC. (c) Cumulative DEX-P releases in different groups indicated in the figure. Reprinted with permission from ref 650. Copyright 2015 American Chemical Society. BL


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multiple ROS-scavenging capability (toward O2•−, H2O2, and HClO),644 presenting superior therapeutic efficacies in murine models of inflammatory diseases, evidencing their application potential in future clinical treatment. Very recently, Bao et al. prepared biodegradable polydopamine nanoparticles as efficient ROS scavengers for the treatment of periodontal inflammation (Figure 67a).645 The polyphenol structure of polydopamine nanoparticles endows them with antioxidant activities toward O2•− and H2O2, guaranteeing high therapeutic efficacy. In addition to organic antioxidative nanosystems, inorganic nanozymes with intrinsic catalytic ROS-scavenging capabilities have also been applied for the treatment of inflammation. Hirst et al. first demonstrated the anti-inflammatory properties of CeO2 nanoparticles in 2009, which was associated with the downregulation of pro-inflammatory inducible nitric oxide synthase expression in J774A.1 macrophages.646 Very recently, Soh et al. fabricated ceria-zirconia (CZ) composite nanozymes with enhanced catalytic activity for ROS depletion and sepsis treatment (Figure 67b).647 The conversion of Ce4+ to Ce3+ is energetically unfavorable in pristine CeO2, while Zr4+ doping in CeO2 facilitates the conversion between the two oxidation states as well as maintains higher Ce3+-to-Ce4+ ratio, thus enhancing the catalytic ROS-depletion performance. In addition, Chen et al. used carbon quantum dots as antioxidative nanocatalysts to scavenge •OH and H2O2 for inflammation treatment.648 They employed a self-healing hydrogel prepared from N-carboxyethyl chitosan and sodium alginate dialdehyde, to encapsulate carbon quantum dots for conferring localized reloadable capability, thus to favor their repeated administration in pathological lesions. 4.2.2. Anti-inflammatory Nanoreactors Responsive to Endogenous ROS. Benefiting from the development of CDR, many nanosystems have also been fabricated with ROS responsiveness for controlled anti-inflammatory drug release within pathological regions.649 As a typical paradigm, Chung et al. first constructed ultrasensitive H2O2-responsive gas-generating nanoreactors for localized osteoarthritis inhibition (Figure 68).650 Such a nanosystem was fabricated by encapsulating ethanol, iron salt (FeCl2), sodium bicarbonate (SBC), and the anti-inflammatory drug dexamethasone sodium phosphate (DEX-P) into PLGA. The overexpressed H2O2 in inflamed joints can diffuse into the PLGA shell and oxidize the encapsulated ethanol into acetic acid in the presence of Fe2+,651 creating an acidic environment to facilitate the decomposition of SBC and the generation of CO2 bubbles. The resulted pressure elevation leads to the disruption of the PLGA shell, facilitating the release of inner antiarthritic DEX-P to the lesion regions. In vivo experiment indicated that most of the articular cartilage presented strong aggrecan and proteoglycan expressions after the treatment, demonstrating that osteoarthritis had been successfully inhibited by the nanosystem. Such a site-specific drug release strategy can also be applied for the treatment of other inflammation-associated diseases. Feng et al. have fabricated a redox-active nanosystem responsive to the inflammatory microenvironment for the treatment of arterial restenosis.652 In this work, β-cyclodextrin was utilized as a pH/H2O2-responsive carrier material, to enable the preferential release of rapamycin (RAP) in the inflamed regions. These nanoparticles could be effectively internalized by rat vascular smooth muscle cells, significantly potentiating the therapeutic performance of RAP. After intravenous injection, the accumulation of nanoparticles at

the injured site of the carotid artery was observed (passive targeting), which may be attributed to the enhanced endothelial permeability of the artery after balloon injury.653,654 Moreover, the surface electric potential of the as-fabricated nanomedicine might further contribute to their significant targeting effect (active targeting).655 This paradigm takes full advantage of inflammatory microenvironment to facilitate targeted transport and site-specific drug release, providing a new approach for the design of a next-generation smart CDR nanosystem. In addition to the conventional pharmaceutical molecules, other biomacromolecules, such as nucleic acids, have also been engineered into CDR nanosystems for anti-inflammatory nanotherapy. Small interfering RNAs (siRNAs) against proinflammatory cytokines have been first applied to treat intestinal inflammation in 2008.656 However, these orally administrated siRNAs suffer from the turbulence of the harsh environment in the gastrointestinal tract, while the systemic depletion of cytokines will also result in severe side effects. To cope with these issues, Wilson and his co-workers fabricated ROS-responsive, orally delivered thioketal nanoparticles (TKNs) for controlled release of siRNAs against the proinflammatory cytokine tumor necrosis factor-alpha (TNFα) in the region of intestinal inflammation (Figure 69).657 These bioresponsive nanoparticles were prepared from poly(1,4-phenyleneacetone dimethylene thioketal) (PPADT), which contains ROS-active thioketal linkages.658 Importantly, PPADT are stable against protease-catalyzed degradation,658,659 guaranteeing that TKNs are stable in the gastrointestinal tract

Figure 69. ROS-responsive, orally delivered thioketal nanoparticles (TKNs) for controlled localization of small interfering RNAs (siRNAs) in the inflammation region. (a) Synthetic strategy and SEM image of as-designed TNF-α-siRNA-loaded TKNs (denoted as TNF-α-TKNs). Scale bar, 1.5 μm. (b) Therapeutic mechanisms of TNF-α-TKNs. (c) Acetal exchange reaction for the synthesis of PPADT. PTSA, para-toluene sulfonic acid. Reprinted with permission from ref 657. Copyright 2010 Nature Publishing Group. BM


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Figure 70. Light-activated in situ H2 generation for ROS depletion in tissue inflammation. (a) Design rationale, therapeutic concept, physicochemical principle, and intracellular mechanism of the photoresponsive nanoreactor. (b) US imaging of H2 bubble generation in bulk solution (BS) and nanoreactor (NR) dispersion under prolonged laser irradiation. (c) Comparison of H2 generation in BS and NR dispersion after laser irradiation. (d) •OH scavenging activities in BS and NR with or without laser irradiation. *P < 0.05. HORAC, hydroxyl radical antioxidant capacity. Reprinted with permission from ref 660. Copyright 2017 American Chemical Society.

Figure 71. Schematic illustration for the application of nanoplatforms in the prevention and treatment of cardiovascular diseases. Reprinted with permission from ref 665. Copyright 2017 Nature Publishing Group.

a sequential reaction nanosystem. Upon laser irradiation, photons are absorbed by Chla, which will accept a new electron from AA and return to its ground state.661 Then, Au nanoparticles collect the electrons from the Chla and the protons from the oxidized AA for the generation of H2,662 providing a gaseous ROS scavenger to reduce intracellular pathological •OH into H2O.663 Such a therapeutic strategy leaves other physiological ROS (such as H2O2 and O2•−) unaffected, thus maintaining normal physiological activities. Histological examinations of inflamed tissues evidence that the prepared photoresponsive H2-generating nanosystem can effectively reduce oxidative stress in pathological regions, indicating its great potential for anti-inflammatory therapy. It is worth noting that, although significant progresses have been made in the past two decades in elucidating the underlying pathogenesis of inflammation, the treatment regimen of inflammation-associated dysfunctions, however, is still in its infancy. It is expected the more feasible ROS-based therapeutic nanosystems will be fabricated for better inflammation management.

to protect inner siRNA from exogenous turbulence. When these orally administrated nanoformulations arrive at inflammation regions, the breakage of thioketal linkages facilitates the nanoparticle degradation and subsequent TNF-α-siRNA release, which downregulates the expression of TNF-α mRNA in the colon to protect mice from ulcerative colitis. This CDR strategy provides a potent therapeutic approach to target upstream pathogenesis (TNF-α mRNA expression) for efficient inflammation treatment, which is also instructive for future research in the design of advanced anti-inflammatory nanomedicine. 4.2.3. Anti-inflammatory Nanoreactors Responsive to Exogenous Stimulus. Exogenous manipulation has also been introduced in anti-inflammatory therapy to effectively regulate the therapeutic process for an optimized outcome. As a typical paradigm, Wan et al. recently prepared an elaborately engineered nanoreactor to favor light-activated in situ H2 generation for ROS depletion in tissue inflammation (Figure 70).660 In this work, chlorophyll a (Chla), L-ascorbic acid (AA), and Au nanoparticles are encapsulated in liposomes to fabricate BN


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Figure 72. GO flakes as a cellular adhesive to protect implanted cells from anoikis for MI treatment. (a) TEM image of a representative GO flake. Scale bar, 1 μm. (b) Viability assay of mesenchymal stem cells (MSCs) cultured for 3 days with the addition of GO flakes. *P < 0.05. (c) Therapeutic concept and corresponding biological mechanisms of GO flakes-augmented cell adhesion and cardiac repair. Reprinted with permission from ref 695. Copyright 2015 American Chemical Society.

4.3. Cardiovascular Diseases

recent report which utilizes genetic pathways to activate the antioxidant response for ROS scavenging,674 the therapeutic modalities against cardiovascular diseases have become ever diversified, and therefore, in this section, we will present this paradigm to give implications on the future integration of nanotechnology and genetic engineering for better therapeutic outcomes of cardiovascular dysfunctions. 4.3.1. Nanoplatforms Facilitate Cell Adhesion in ROS Microenvironment. Mesenchymal stem cell (MSC) implantation has been developed as a potential strategy for MI treatment by facilitating the secretion of paracrine factors.675−677 However, the poor survival of MSCs has greatly compromised their therapeutic benefit,678 which is closely associated with the overproduction of ROS in the infarcted region after reperfusion.679,680 These excess ROS impede the adhesion of MSCs to the myocardium extracellular matrix (ECM),681 leading to the apoptosis of MSCs (i.e., anoikis) due to the lack of MSC−ECM interaction, thereby deteriorating the therapeutic efficacy of MSC implantation in MI treatment. 2D inorganic materials have been explored for years,682−685 among which GO sheets have been extensively applied in biomedicine based on their unique surface chemistry.686−693 Intriguingly, they are capable of adsorbing ECM proteins from serum, facilitating cell adhesion on their 2D topographical surface by providing additional cell−ECM interaction.694 In light of such a unique cytoprotective effect of GO sheets, Park et al. prepared GO flakes as a cellular adhesive to protect implanted MSCs from anoikis in ROS-abundant injured myocardium for MI treatment (Figure 72).695 In this study, MSCs were allowed to adhere on GO flakes prior to implantation, thus to enable the cell−ECM interaction between MSCs and the ECM adsorbed on GO flakes. Moreover, this process can also enhance the paracrine secretion from the MSCs after implantation, which further promotes cardiac function restoration. Differing from all the aforementioned ROS-based nanoplatforms that take advantage of their intrinsic material chemistry to confer ROS-regulating capabilities or

Cardiovascular disease is a major cause of mortality worldwide, and its prognosis remains poor.664,665 Atherosclerosis is the most common pathogeny of cardiovascular diseases, especially myocardial infarction (MI, known as heart attack).666 Both experimental and clinical evidence indicate that vascular oxidative stress, which is associated with a few cardiovascular risk factors (e.g., diabetes mellitus,667 hypertension,668 hypercholesterolemia,669 etc.), can predispose patients to the development of atherosclerosis.670 The activation of ROSgenerating enzyme systems (NOX, XO, Mito-ETC, etc.) and/ or the weakening of ROS-detoxifying systems (GSH, uric acid, vitamins, poly phenolic compounds, etc.) will lead to oxidative stress intensification and subsequent inactivation of vascular NO, a key regulator of endothelial functions, through the rapid oxidation of NO by O2•−, or dysfunction of endothelial NO synthase via oxidative damage, which further contributes to O2•− generaion.557 On account of the significant role that NO plays in maintaining vascular homeostasis (e.g., inducing vaso dilation, inhibiting platelet aggregation, and decreasing proinflammatory genes expression671), such a ROS-induced NO dyshomeostasis may activate multiple proinflammatory and proatherosclerotic pathways, accompanied by the upregulated expression of pathogenic gene products, which is the major molecular basis of atherosclerosis.557,672 Demonstrations on the pathogenicity of excessive ROS have also inspired scientists to fabricate feasible nanoplatforms for the prevention and treatment of cardiovascular disease (Figure 71).665 In general, these ROS-based nanosystems exert their therapeutic effects via the two following approaches: (1) sequestration of ROS microenvironment to protect implanted cells from ROS-induced anoikis; (2) direct depletion of excessive ROS to mitigate endothelial dysfunction. Given there is no innate mechanism in angiocarpy that facilitates the passive/active targeting of nanomedicines toward lesion areas after systemic administration, generally these nanoplatforms are locally administered within pathological tissues.673 Based on a BO


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Figure 73. Multifunctional biomaterials with ROS-scavenging capability for cardiac repair. (a) Macrophage-targeting/polarizing GO complex (MGC) as efficient antioxidant to modulate the immune environment for MI treatment. (a1) Cellular mechanism to elucidate the therapeutic effects of interleukin-4 plasmid DNA (IL-4 pDNA)-loaded MGC (MGC/IL-4 pDNA). (a2) Interdependent relationship among the ROS depletion, inflammation attenuation, and phenotype transformation in MI treatment after the administration of MGC/IL-4 pDNA. Reprinted with permission from ref 697. Copyright 2018 American Chemical Society. (b) Fullerenol nanoparticles-reinforced injectable alginate hydrogel to regulate ROS level and facilitate cardiomyogenic differentiation of brown adipose-derived stem cells (BADSCs). (b1) Biochemical mechanisms of fullerenol/alginate hydrogel-enabled BADSCs delivery. (b2) Digital photographs and 3D model of fullerenol/alginate hydrogel. Reprinted with permission from ref 703. Copyright 2017 American Chemical Society.

ROS responsiveness for exerting their corresponding therapeutic functions, the treatment strategy in this work is based on the unique biophysical characteristics of GO to facilitate the sequestration of ROS microenvironment and supplementation of additional ECM for assisting the protection of MSCs, finally contributing to the enhancement of cardiac repair effect. 4.3.2. Therapeutic Platforms Scavenge Excessive ROS To Augment Heart Repair. The second approach for mitigating cardiovascular dysfunction is the direct depletion of excessive ROS by antioxidative nanosystems. A 2012 study by Pagliari et al. first reported that CeO2 nanoparticles could protect cardiac progenitor cells from oxidative stress.696 In this work, internalized CeO2 nanoparticles were able to protect cardiac progenitor cells from H2O2-induced cytotoxicity for more than 7 days, indicating the great potential of the inorganic nanozyme in cardiac repair. Recently, Han et al. also used GO as an antioxidant to attenuate inflammatory polarization of macrophages for MI therapy (Figure 73a).697 Given ROS overexpression during MI can initiate inflammatory activation of macrophages (M1 phenotype) and facilitate their migration to the infarct,698−700 the downregulation of ROS levels by GO is able to mitigate postinfarct inflammation and benefit cardiac repair. Moreover, in this work, interleukin-4 plasmid DNA (IL4 pDNA) was loaded on the planar surface of GO to enable an earlier polarization shift of macrophages from proinflammatory M1 to their regenerative counterparts (i.e., M2 phenotype), which not only provides a complementary effect to facilitate inflammation attenuation but also enhances the secretion of cardiac regenerative cytokines for synergistic MI treatment. This work integrates antioxidative therapy and immunotherapy for the cooperative augmentation of therapeutic effect, paving a new way for MI treatment.

Based on the localized manner of drug administration in the treatment of cardiovascular disease, encapsulating molecular or nanoscale antioxidants into hydrogel preinjection is an effective approach to improve therapeutic efficacy by confining and fixing inner antioxidative agents within lesion regions.701 Moreover, these injectable hydrogels can be specifically tailored to mimic 3D cardiac ECM to provide an appropriate stereoscopic microenvironment with regenerative biochemical cues, thus facilitating cell adhesion, proliferation, and/or maturation. Li et al. first fabricated a chitosan-GSH-based injectable composite hydrogel for suppressing oxidative damage in cardiomyocytes.702 They conjugated GSH on the chitosan chloride chain via amide bonding, thus to fix these antioxidative GSH molecules to ensure minimized leakage. Such a chitosanGSH conjugate can not only effectively scavenge O2•− and • OH even at relatively high concentrations but also present excellent biocompatibility to favor the adhesion and survival of cardiomyocytes based on the unique bioactive properties of chitosan. Additionally, Hao et al. reported a fullerenol nanoparticlereinforced injectable alginate hydrogel for cardiac repair, which can not only downregulate ROS level in lesion regions but also facilitate cardiomyogenic differentiation of brown adiposederived stem cells (BADSCs) seeded in the composite hydrogel (Figure 73b).703 As a typical antioxidative nanozyme, fullerenol confers appreciable ROS-scavenging ability to mitigate oxidant damage, during which JNK signaling pathways were inhibited but ERK and p38 signaling pathways were activated, further promoting the survival and proliferative capacity of BADSCs. Moreover, the cardiomyogenic differentiation capacity of BADSCs can also be elevated by the fullerenol nanoparticles even under ROS microenvironment, presenting a synergistic therapeutic effect for cardiac repair. In vivo results suggested BP


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Figure 74. Paired-like homeodomain transcription factor 2 (Pitx2) activates the antioxidant response after cardiac injury for MI treatment. (a) Immunofluorescent staining of Pitx2 (green) and 4′,6-diamidino-2-phenylindole (DAPI, blue) in P19 cells with or without vehicle or H2O2 addition. SiNrf2, siRNA targeting Nrf2. Arrows indicate cytoplasmic staining, while arrowheads represent nuclear staining. (b) Sankey diagram showing direct target genes of Pitx2. ChIP-seq, chromatin immunoprecipitation followed by sequencing; FDR, false discovery rate; OXPHOS, oxidative phosphorylation. (c, d) ROS staining (green) of apical border zone in control (left) and Pitx2 conditional knockout (CKO, right) mice at low (c) and high (d) magnifications. MF20 (myosin heavy chain antibody), red; DAPI, blue. DPR, days postresection. Reprinted with permission from ref 674. Copyright 2016 Nature Publishing Group.

outcome of cardiac repair was further evidenced by genomic analyses, which indicated that Pitx2 could activate genes encoding electron transport chain components and ROS scavengers to protect cells from oxidative damage. Importantly, in vitro binding assays and coimmunoprecipitation of endogenous cardiac proteins have evidently demonstrated the Pitx2-Yap interaction is crucial for Hippo-deficient cardiac regeneration, which is closely associated with gene activation for maintaining redox balance. Thus, Pitx2 has been evidenced to be essential for cardiac repair, which constitutes a solid theoretical foundation to design next-generation potent therapeutic medicines (such as multifunctional nanomedicines) for efficient treatment of MI by targeting Pitx2. ROS-based therapeutic platforms for cardiovascular diseases are still in their early stage. The complexity of pathogenesis, as well as the lack of innate targeting mechanism, make the treatment of cardiovascular diseases even more difficult. However, encouraged by the recent advances in nanotechnology, biology, and tissue engineering, researchers can develop more systematic treatment regimens to improve the therapeutic outcomes based on the clarification of the upstream genomic regulatory mechanisms, as well as downstream clinical symptoms.

that the established composite hydrogel could effectively mitigate oxidative stress in the MI zone, improve the survival of BADSCs, and promote angiogenesis as well, which in turn contribute to the recovery of cardiac functions. Thus, the fullerenol/alginate hydrogel can serve as a robust delivery vehicle of BADSCs in the treatment of MI, which will inspire researchers to integrate materials science and cell engineering to establish more feasible therapeutic platforms for efficient cardiac repair. 4.3.3. Genetic Pathways Activate the Antioxidant Response. Recent marked breakthroughs in uncovering the genomic mechanisms of cardiac repair have further pushed forward the development of advanced therapeutic modalities for efficient MI treatment. If we could precisely modulate the upstream genomic regulatory mechanisms involved in the pathogenesis/recovery of cardiovascular disease, such as ROS/ antioxidant-related genomic pathways, the downstream cardiovascular dysfunctions would be probably eradicated. As a pioneering study, Tao et al. first demonstrated that Paired-like homeodomain transcription factor 2 (Pitx2) can activate the antioxidant response after cardiac injury for the treatment of MI (Figure 74).674 By evaluating an established Hippo-deficient heart regeneration mouse model, they manifested that the expression of Pitx2 could be induced in border zone ventricular cardiomyocyte nuclei of adult mouse hearts after MI, capable of facilitating the regeneration process. Comparatively, neonatal mouse hearts failed to self-repair after apex resection due to the leakage of Pitx2. Such a vital role of Pitx2 in determining the

4.4. Bacterial infection

Microorganisms engage in complex interactions with other organisms that coexist in nature.562,704 For example, bacteria can interact with human bodies either synergistically or antagonistically, and they have a significant role in human BQ


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health and pathogenesis.705 The positive effects of bacteria on humans have been utilized for disease prevention and have even been developed as microorganism-based therapeutics,706 while the negative ones may influence normal metabolic processes and result in pathological dysfunctions, which can be collectively referred to as bacterial infection.707 These downstream diseases as a result of pathogenic auxotrophic bacteria may present serious global challenges threatening public health,708 underscoring the need to take medical actions accordingly to cope with such a dilemma. The 1940s, 50s, and 60s have witnessed the rapid development of antibiotics, which were highly expected to be the terminators of all bacterial disease.709 However, this expectation has been quickly tempered by the emergence of MDR among bacteria.710 For example, enterobacteriaceae, such as E. coli and Klebsiella pneumoniae (KPN), are antibioticresistant and were recently designated as first-rank bacterial pathogens by the World Health Organization.711 Therefore, it is of great importance to develop novel feasible antimicrobials to overcome MDR of bacteria for effective antibacterial therapy. In the past decade, numbers of antibacterial nanoplatforms have been fabricated to inactivate MDR bacteria for therapeutic applications, among which ROS-generating nanoplatforms have attracted broad attention (Figure 75). In fact, analogous to

driven ROS generation. We will focus on the unique redox activities of these therapeutic systems, to render readers a better understanding of the therapeutic mechanisms and corresponding therapeutic concepts. 4.4.1. Chemo-Driven ROS Generation by Nanozymes. Analogous to cancer CDT, antibacterial therapy can also utilize catalytic nanomaterials to generate toxic ROS and bring oxidative damage to bacteria. Typically, nanozymes with intrinsic peroxidase-like activities have also been extensively applied for inhibiting bacterial infection by reacting with an added low concentration of H2O2 to catalyze the generation of • OH (Fenton-like reactions).714 Here, H2O2 serves as an extrinsic substrate for sustained enzymatic reactions, which differs from the case in cancer CDT in which H2O2 acts as an endogenous biosynthetic trigger to activate the catalytic reactions specifically within tumor. As an increasing number of inorganic nanomaterials have been evidenced to be peroxidase mimics, several representative catalytic nanozymes, such as Fe3O4 nanoparticles,715,716 Fe3S4/Fe1−xS nanoparticles,717 V2O5 nanowires,118,712 graphene quantum dots,718 GO nanosheets,719 MoS2 nanosheets,720,721 g-C3N4 nanosheets,722 Pd nanocrystals,723 etc., have also been demonstrated of significant antibacterial effects in the presence of H2O2. It is noted that such a meticulous cooperation between nanozyme and H2O2 also necessitates high catalytic efficiency of nanozyme to lower the H2O2 usage in antibacterial therapy for circumventing unnecessary biosafety issues. On account of the diversity of pathogenic bacteria and the complexity of underlying pathogenesis, therapeutic protocols should be properly tailored based on the requirement of specific biological scenarios. For example, dental biofilms develop when extrinsic Streptococcus mutans, and/or other bacteria, accumulate on a tooth surface and create a highly acidic microenvironment, which results in the gradual aciddissolution of enamel-apatite on teeth and the subsequent dental caries (tooth decay). To address this issue, Gao et al. first used Fe3O4 nanocatalysts in combination with H2O2 to suppress dental caries by promoting the biofilm matrix degradation and enhancing bacterial killing (Figure 76).716 The intrinsic peroxidase-like activities of Fe3O4 nanoparticles favor the catalytic generation of strong oxidizing •OH in acidic niches of caries-causing biofilm to trigger the degradation of protective ECM and the death of Streptococcus mutans. Moreover, this catalytic therapeutic system is also capable of inhibiting hydroxyapatite demineralization in acidic conditions by creating a barrier of ferric phosphate, which will mitigate the severity of carious lesions in vivo. Such a catalytic strategy can also be integrated with other antibacterial modalities for a synergistic germicidal outcome. As a typical paradigm, Yin et al. first utilized PEGylated MoS2 nanosheets as bifunctional therapeutic platforms for synergistic catalytic/photothermal treatment of wound infections.721 Based on the intrinsic peroxidase-like activity and photothermalconversion capability of MoS2,317,724 the combination between catalytic •OH generation and NIR photothermal effect is applicable to enhance the ultimate antibacterial efficacy. Moreover, •OH-induced GSH oxidation can be accelerated by local hyperthermia generated in the photothermal process to facilitate the breakdown of the intercellular antioxidant defense system of bacteria [E. coli and Bacillus subtilis (B. subtilis) in this work], further improving the therapeutic effect. In addition to the aforementioned peroxidase-mimetic nanozymes, recently, V2O5 nanowires with vanadium haloper-

Figure 75. Antibacterial process of nanoparticles by initiating ROS production. (a) Nanoparticles (yellow-green rods) are applied onto a topographical surface. (b) Bacterial attack occurs on the surface. (c) Nanoparticles enable ROS generation under the activation of exogenous/endogenous triggers. (d) The released ROS induce oxidative damage on bacteria. Reprinted with permission from ref 712. Copyright 2012 Nature Publishing Group.

other eukaryocytes, bacteria also possess an endogenous antioxidant defense system (CAT, SOD, peroxiredoxins, etc.) to neutralize extrinsic aberrant oxidants and convert them to harmless products.561,713 Therefore, to obtain a desirable antibacterial outcome, high ROS-generating efficiency of nanomedicine is the prerequisite to guarantee the elevation of oxidative stress significantly over the tolerability threshold of bacteria and thus to exert a therapeutic effect. In this section, we will elucidate the state-of-the-art studies concerning the recent advances in this field: (1) nanozymes with peroxidaselike activities for chemo-driven ROS generation; (2) semiconductors with unique energy band structures for photodriven ROS generation; (3) electrochemiluminescence for electricBR


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Figure 76. Fe3O4 nanocatalysts with intrinsic peroxidase-like activity to suppress dental caries. Reprinted with permission from ref 716. Copyright 2016 Elsevier Ltd.

Figure 77. V2O5 nanowires with vanadium haloperoxidase (V-HPOs)-like activity for antibacterial applications. (a) Michaelis−Menten behavior observed at different H2O2 concentrations. (b) pH-dependent bromination reaction catalyzed by V2O5 nanowires. (c) Stability evaluations of V2O5 nanowires. Left: digital photograph of reaction vial. Right: TEM image of V2O5 nanowires. (d) Proposed catalytic mechanism for the V2O5 nanowires in the presence of Br− and H2O2. (e) Representative digital images of different groups revealing the effect of the catalytic V2O5 nanowires on the growth of Gram-negative (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) bacteria. NW, nanowire. Reprinted with permission from ref 712. Copyright 2012 Nature Publishing Group.

Gram-negative E. coli and 96% for Gram-positive S. aureus) have been observed in the presence of V2O5 nanowires, Br−, and H2O2 compared to bacteria grown in the absence of one or more additives, indicating that the synergy among the three reactants is required to obtain the V-HPOs-like activity for strengthened biocidal effect. This paradigm provides an alternative approach for the treatment of bacterial infection due to its unique reaction conditions (pH > 7) and multiple ROS generations (HBrO and 1O2) to meet the specific

oxidase (V-HPOs)-like activity have also been reported to be capable of generating HBrO and 1O2 concurrently for inducing a strong bactericidal effect (Figure 77).712 In the presence of Br− and H2O2 (pH = 8.3), the surface of V2O5 nanowires undergoes nucleophilic attack, peroxo complex intermediate formation and halide attack, resulting in the catalytic generation of HBrO. Moreover, in the absence of an organic acceptor, HBrO may react with another H2O2 molecule to yield 1O2, exerting stronger antibacterial activity to prevent biofilm formation. Significant decreases in bacterial growth (78% for BS


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Figure 78. Vertically aligned MoS2 nanofilms harvest visible light for bacteria inactivation. (a) ROS-generating potentials with respect to the vacuum level (left), as well as visible-light-triggered ROS generation by few-layered vertically aligned MoS2 (FLV-MoS2) films for bacteria inactivation. (b) TEM image (top view) of FLV-MoS2 showing its vertically standing characteristic. Scale bar, 10 nm. (c) A photo of FLV-MoS2 film with an Au line pattern. (d) Schematic illustration showing the enhancement of electron−hole separation by Cu/Au deposition. GC, glassy carbon. (e) Photoinactivation performances of Cu-MoS2, Au-MoS2, and pristine FLV-MoS2. (f) Comparison of photoinactivation performances of Cu-MoS2 with other photocatalysts reported using E. coli for evaluation. (1) Cu-MoS2 (referenced), (2) TiO2−CdS, (3) ZnO/Cu, (4) GO-CdS, (5) BV, (6) GO-C3N4, (7) SGO-ZnO-Ag. NA, not available. Reprinted with permission from ref 737. Copyright 2016 Nature Publishing Group.

sary for enhanced •OH-generating efficiency and oxidative damage on pathogenic bacteria. 4.4.2. Photodriven ROS Generation by Semiconductors. The second methodology for antibacterial therapy is to take advantage of the photosensitiveness of nanomedicines for light-triggered ROS generation, which is the same as PDT in physicochemical principles but varied in treatment objects. Typically, semiconductor nanomaterials have been extensively developed for light-activated antibacterial therapy based on their tunable photoelectric properties that promote catalytic ROS generation. Courtney et al. first demonstrated that CdTe quantum dots (with a band gap energy of 2.4 eV, CdTe-2.4) could induce light-activated toxicity in several MDR bacterial strains, including methicillin-resistant S. aureus, carbapenemresistant E. coli, and extended-spectrum β-lactamase-producing KPN and Salmonella typhimurium.725 Moreover, they further pointed out that the phototoxicity of CdTe-2.4 quantum dots was controlled by the redox potentials of charge carriers, which could be tuned through changing the particle size. In a successional work, the researchers also engineered CdTe-2.4 quantum dots to generate O2•− and potentiate antibiotic activity in MDR isolates for synergistically enhanced antimicrobial therapy.726

requirements of antibacterial applications in different biological environments. It is worth noting that the unique catalytic activities of nanozymes are determined by their structural and compositional characteristics, and variations in these features may result in distinct antibacterial activities. For example, Fang et al. recently reported that the bactericidal activities of Pdnanocrystals were strongly associated with their exposed facet.723 {100}-faceted Pd cubes present higher oxidase and peroxidase-like activities than {111}-faceted Pd octahedrons, leading to higher biocidal efficacies against Gram-positive bacteria. However, for Gram-negative bacteria, a reverse trend of antibacterial activity was observed, where Pd octahedrons displayed stronger membrane-penetration capacities than Pd nanocubes, thereby exhibiting higher antibacterial activities than the latter. In addition to the microscopic structures, composition of nanozymes is also a critical factor governing catalytic activities and consequent therapeutic efficacies. Wang et al. first discovered that the hybridization of g-C3N4 nanosheets by Au nanoparticles can significantly enhance the peroxidase-like activity of g-C3N4, due to the positive synergistic coupling effect of Au nanoparticles in stabilizing • OH radicals.722 Thus, to achieve a better therapeutic outcome, structural/compositional regulations of nanozymes are necesBT


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Figure 79. Functionalized semiconductors for enhanced ROS generation and antibacterial effects. (a) ZnO/Au hybrid nanostructures. (a1) TEM images of ZnO/Au hybrid nanoparticles. (a2) HRTEM image of the sample from (a1). (a3) Mechanistic proposal for ROS generation and detection. DMSO, dimethyl sulfoxide; CPH, 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine. Reprinted with permission from ref 738. Copyright 2014 American Chemical Society. (b) Ag/Ag@AgCl/ZnO hybrid nanostructures. (b1) Schematic illustration for light-triggered generation of •OH and O21, as well as ion release to facilitate wound healing. (b2, b3) Antibacterial efficacies of the hybrid systems in killing E. coli (b2) and S. aureus (b3) under the irradiation of sunlight for 20 min. Reprinted with permission from ref 739. Copyright 2014 American Chemical Society.

Figure 80. Electric-driven electrochemiluminescence (ECL)-based system for endogenous PS excitation, controllable ROS generation, and persistent antibacterial effect. (a) Electrochemical and photochemical mechanisms of the ECL-based system for pathogenic bacteria killing. (b) Experimental setup, SEM image of the composite hydrogel, as well as its bending and stretching deformation modes. Scale bar: left, 5 μm; right, 1 μm. Reprinted with permission from ref 740. Copyright 2018 American Chemical Society.

capability. The fabricated FLV-MoS2 nanofilms showed a ∼15 times higher bacteria photoinactivation efficiency compared with that of bulk MoS2, demonstrating the vital role of dimension transition of MoS2 (from 3D to 2D) in improving its photocatalytic performance. Given semiconductors are nonspecific in promoting ROS generation among other competing reactions [such as hydrogen evolution reactions (HER), OER, etc.], additional functional materials (Cu or Au) were modified on the surface of MoS2 to improve the electron−hole separation efficiency and ROS-generating performance. With the deposition of 5-nm-thick Cu or Au, FLV-MoS2 nanofilms presented rapid inactivation of >99.999% E. coli in as short as 20 and 60 min, respectively, demonstrating remarkable antibacterial efficacy. The above report indicates that proper functionalization of semiconductors is beneficial in regulating the separation of charge carriers for enhanced ROS production capability and

2D transition metal dichalcogenides, such as MoS2 nanosheets, have been extensively developed in optoelectronics, energy storage, and biomedicines in the past several years.727−735 By decreasing the thickness of MoS2 from bulk material to a single layer, its bandgap changes from 1.3 to 1.9 eV,736 making it a robust photocatalyst to harvest the whole spectrum of visible light for efficient electron−hole separation and ROS generation. In a recent exploration, Liu et al. first utilized few-layered vertically aligned MoS2 (FLV-MoS2) nanofilms to make full use of visible light for enhanced photocatalytic bacterial inactivation (Figure 78).737 The significantly decreased thickness of FLV-MoS2 nanofilms facilitated the diffusion of electrons and holes to their planar surface, which further promoted the electron−hole separation. Moreover, such a 2D topographical morphology provided a large specific surface area to favor their interaction with ambient milieu for enhanced ROS-generating efficiency and antibacterial BU


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Figure 81. Femtosecond laser initiates ROS generation for noninvasive permanent vision correction. (a) Proposed laser-assisted therapeutic process, which involves the low-density plasma generation, ROS production, and cross-link formation. (b) ESR spectra demonstrating the •OH and O2•− generation via ionization of the solution. (c) Fluorescence spectra of corneal samples with or without laser treatment. (d) Schematic illustration of the oxidative modification of tyrosine for dityrosine cross-link generation. Reprinted with permission from ref 741. Copyright 2018 Nature Publishing Group.

neutrophils for immunoregulatory effects, finally accelerating wound healing of established animal models. The two paradigms will inspire researchers to take full advantage of the cooperative interactions between different nanomaterials, to design more potent photosensitive agents for efficient bacteria inactivation. 4.4.3. Electric-Driven ROS Generation by Electrochemiluminescence. Besides industrial sectors, current biomedical fields are also considering how to fully make use of electric energy to benefit the health of human beings. Very recently, Liu et al. first constructed an electrochemiluminescence (ECL)-based luminous system for the inactivation of pathogenic bacteria (Figure 80).740 In this system, the anodic oxidation of 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol) on the surface of a glassy carbon electrode (GCE) enables the generated reactive intermediate to react with O2•− (produced by oxidization of H2O2) and form the excited 3aminophthalate dianion, which returns to its ground state with light emission (i.e., ECL), further activating oligo(p-phenylenevinylene) (OPV, as PS) for ROS generation. Additionally, in this study, the researchers utilized polyacrylamide hydrogel

bacteria inactivation efficacy. In fact, a report in 2013 has extensively elucidated the synergy between host semiconducting materials and guest electron-accepting materials by exemplifying fabricated ZnO/Au hybrid nanostructures (Figure 79a).738 As a typical wide band gap semiconductor, ZnO has the conduction and valence band edges at −0.2 and 3.0 V, respectively, which enables the holes to react with H2O to produce •OH and enables the electrons to react with O2 to generate O2•−. However, the fast recombination between the charge carriers diminishes the generation of ROS in ZnO. To overcome such a limitation, in this work, Au was deposited on the surface of ZnO, which not only enhanced light absorption via the surface plasmon resonance (SPR) effect but also significantly promoted charge carrier separation, thus facilitating ROS generation and bacteria inactivation. Additionally, Mao et al. fabricated Ag/Ag@AgCl/ZnO hybrid nanostructure for antibacterial therapy (Figure 79b).739 The coupling of Ag/ Ag@AgCl accelerates charge separation in ZnO to facilitate photocatalytic ROS generation. Moreover, in vivo results demonstrate that the sustained releases of Ag+ and Zn2+ from the hybrid nanostructure will recruit a large number of BV


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Table 8. Summary of the Representative ROS-Based Therapeutic Platforms for Noncancerous Pathological Abnormalities therapeutic platforms

ROS types

Congo red/Rutin-MNP

H2O2

SHp-RBC-NP

H2O2

Angiopep-2 and edaravone-loaded CeO2, TPP-CeO2

O2•−, H2O2

CeO2, IONP, MBloaded MSNs CeO2 nanoparticles

O2•−, H2O2

O2•−, H2O2

IONPs

O2•−, H2O2, • OH H2O2

GO quantum dots

H2O2

Engineered-exosomes Melanin nanoparticles

H2O2 O2•−, H2O2, • OH O2•− • OH

Au@POMD nanozymes BP nanosheets Tpl-loaded βcyclodextrin Polydopamine nanoparticles

O2•−, H2O2 all ROS

working mechanisms

600

Ischemic stroke treatment Ischemic stroke treatment

602

SOD-mimetic and CAT-mimetic activities of CeO2 enable sequential ROS depletion; TPP conjugation facilitates mitochondrial localization SOD-mimetic and CAT-mimetic activities of CeO2 enable sequential ROS depletion; MB release inhibits hyperphosphorylated tau aggregation SOD-mimetic and CAT-mimetic activities of CeO2 enable sequential ROS depletion; CeO2 shifts microglial activation from M1 to M2 phenotype

AD treatment

609

AD treatment

613

Neuroprotection

614

CAT-like activity of IONPs enables the decomposition of H2O2 in neutral pH; IONPs diminish αSynuclein accumulation and caspase-3 activation CAT-mimetic activity of GO nanozyme enables the decomposition of H2O2; GO quantum dots inhibit the expression of α-synuclein Engineered-exosomes express CAT in Neuro2A cells for catalytic depletion of intercellular ROS SOD-mimic activity of melanin nanoparticles enables O2•− depletion; H2O2 scavenging nature of melanin; chelating capability of melanin with Cu+

Neurodegenerative disorder therapy Neurotoxicity inhibition PD treatment Ischemic brain protection

615

Hepta-peptides present SOD-like activity for ROS depletion and capture excessive Cu2+ as well BP nanosheets chelate Cu2+ to form BP-Cu complex and protect cells from Cu2+ dyshomeostasisrelated •OH generation H2O2 decomposition by CAT-mimetic β-cyclodextrin and O2•− disproportionation by SODmimetic Tpl molecules Polyphenol structure of polydopamine nanoparticles enables multienzymatic antioxidant activity

AD treatment Neurodegenerative disorder therapy Inflammatory bowel disease treatment Periodontal inflammation treatment Sepsis treatment Inflammation inhibition Localized inflammation inhibition Arterial restenosis treatment Intestinal inflammation inhibition Inflammation inhibition MI therapy

629 635

O2•−, •OH H2O2, •OH

FeCl2-based PLGA HM

H2O2

β-cyclodextrin

H2O2

H2O2-responsiveness of nanoparticles facilitates RAP release in the pathological sites

TKNs

H2O2

H2O2-triggered breakage of thioketal linkages facilitates the degradation of nanoparticles and the release of TNF-α-siRNA to inflammation sites Au nanoparticles collect electrons from the Chla and the protons from the oxidized AA for the generation of H2 gas, which reduces intracellular •OH to H2O GO adsorbs ECM proteins and facilitates MSCs adhesion on its 2D topographical surface by providing additional cell-ECM interaction GO matrix scavenges intracellular ROS; IL-4 pDNA enables a polarization shift from M1 to M2 GSH introduction provides more H atom donor groups to elevate scavenging activity against O2•− and •OH Enzymatic activity of fullerenol endows 3D composite hydrogel with ROS-scavenging capability

IL-4 pDNA-loaded GO chitosan and GSH-based hydrogel fullerenol-loaded hydrogel Pitx2 IONP PEG-MoS2 nanoflowers V2O5 nanowires Pd nanocrystal

•

OH

H2O2 H2O2 O2•−, •OH H2O2, •OH H2O2 • OH •

OH 1

HOBr, O2 OH

• •

Au/g-C3N4 hybrid nanozyme CdTe quantum dots

O2•−

CdTe quantum dots

O2•−

FLV-MoS2

H2O2, O2•−, • OH, 1O2 O2•−, •OH, 1 O2 • OH, 1O2

ZnO/Au hybrid nanoparticles ZnO/AgCl-based hydrogel ECL-based system low-density plasma

OH

1

O2

•

OH

refs

AD treatment

CZ nanoparticles C-dots-based hydrogel

Chla, AA, Au-loaded liposomes GO flakes

applications

H2O2-responsiveness of boronate ester favors controlled release of Rutin within pathological regions H2O2-responsive controlled release of NR2B9C in ischemic neurons; RBC coating prolongs the circulation lifetime of nanoparticle SOD-mimetic and CAT-mimetic activities of CeO2 enable sequential ROS depletion, complementary antioxidative effect of edaravone, targeting capability of angiopep-2

Zr4+ doping facilitates the conversion of Ce4+ to Ce3+ and maintains high Ce3+/Ce4+ ratio Structural defects and active groups on the surface of C-dots facilitate electrons transfer for ROS depletion H2O2 oxidizes ethanol in the presence of Fe2+ to create an acidic environment for SBC decomposition and CO2 generation

608

616 626 627

643 645

647 648 650

652 657 660 695

MI therapy MI therapy

697 702

MI therapy

703

MI therapy Dental caries treatment Wound disinfection

674 716

Biofilm eradication Antibacterial treatment

712 723

Wound disinfection

722

Antibacterial treatment

725


726

Disinfection

737

Holes of semiconducting ZnO react with H2O to generate •OH; electrons react with O2 to produce O2•−


738

ZnO and AgCl act as PSs to generate electron−hole pairs after photon absorption; Ag prevents fast recombination of electron−hole pairs to facilitate ROS generation Overlap between the absorption spectrum of OPV and ECL spectrum enables photosensitization for ROS generation Laser-induced H2O+ reacts with a water molecule for the generation of H3O+ and •OH; the excited water molecule self-dissociates and generates another •OH

Wound disinfection

739


740

Vision correction

741

Pitx2 and Yap interacts and cooperatively activates genes maintaining redox balance Fe3O4 nanozyme catalyzes H2O2 into •OH to trigger protective ECM degradation and bacteria death Peroxidase-like activity of MoS2 enables H2O2 decomposition to generate •OH; photothermal performance of MoS2 further enhances therapeutic effect V-HPOs-like activity of V2O5 nanowires to enable the catalytic generation of HOBr and 1O2 Facet-dependent oxidase and peroxidase-like activities of Pd nanocrystals endow them with excellent antibacterial properties Integration of Au nanoparticles with ultrathin g-C3N4 nanosheets provides excellent peroxidaseactivity CdTe quantum dots generate excited electrons and holes across their nominal energy band gap for O2•− production under light irradiation CdTe quantum dots facilitate O2•− production under light irradiation to potentiate antibiotic activity in highly MDR bacterial pathogen Separation of electron−hole pairs in FLV-MoS2; increased reaction sites facilitate ROS generation and bacteria photoinactivation.

BW

721


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Table 8. continued therapeutic platforms macrophages-derived exosomes

ROS types O2•−, H2O2

working mechanisms NOX2 complexes are secreted from macrophage-derived exosomes to oxidize PTEN for regenerative reprogramming

applications Axonal regeneration

refs 742

subsequent generation of tyrosyl radicals, which can further react with tyrosine or other tyrosyl radicals to form 1,3dityrosine, leading to cross-linking for the spatially resolved alteration of corneal biomechanics. This pioneering work is implemented by employing a femtosecond laser to initiate ROS generation for vision correction, which inspired researchers to conceive other feasible ROS-generating nanosystems to benefit the therapeutic process by enhancing ROS-generating efficiency and mitigating side effects, finally favoring the clinical translation of such an advanced femtosecond laser technology for myopia treatment. When we design proper therapeutic strategies for the treatment of malignant diseases, simultaneous tissue regeneration is also supposed to be taken into consideration for the optimization of the therapeutic outcome. The year 1993 marked the booming growth of research on tissue regeneration when Langer first proposed the concept of “tissue engineering”.744 Since then, numerous technological strategies have been developed to promote tissue regeneration for the recovery of lesion sites.745,746 ROS, as the key signal transduction mediators in biosystem regulating various physiological activities, have attracted broad attention of scientists to utilize such versatile chemical species for facilitating tissue regeneration. A recent remarkable report by Hervera et al. first indicated that ROS could be applied to regulate axonal regeneration through the release of NOX2 complexes into injured axons.742 After spinal injury, exosome containing NOX2 complexes will release from macrophages into axon. Then NOX2 oxidizes phosphatase and tensin homologue deleted on chromosome 10 (PTEN) to stimulate PI3K-phosporylated Akt signaling, thus facilitating regenerative reprogramming. This discovery also lays a solid foundation to utilize biosynthetic exosome-based therapeutic nanoplatform for tissue regeneration in the pathological region. The substantial evolution of ROS science will provide great opportunities to develop novel and feasible strategies for the treatment of various pathological dysfunctions (neurodegenerative disorders, inflammation, vascular diseases, bacterial infection, etc., Table 8). Although most of them are still in their early stages, it is believed that further substantial developments in this field will greatly contribute to the establishment of more robust nanoplatforms for the health of human beings.

to replace the liquid phase in the ECL system to develop a hydrogel-based antimicrobial device. Due to the relatively low reaction rate in the hydrogel, the ECL could last for more than 10 min after charging for only five seconds, making them suitable for persistent antibacterial therapy. Such an ECL strategy applies electric energy to power the ROS-generating process, which is attractive in designing advanced electricdriven nanomedicine for convenient, simple, and controllable antibacterial therapy. On account of the similar mechanisms of ROS-mediated anticancer and antibacterial therapeutics, the design rationale of antibacterial nanomedicines can be inspired from the relatively mature methodologies in cancer therapy. For example, antibacterial therapy can also be integrated with endogenous immunoregulation for individualized synergistic treatment. It is expected that more feasible antibacterial platforms will be fabricated in the future for significantly improved therapeutic effects on bacterial infection. 4.5. Other Diseases

In addition to the aforementioned disease treatments, where redox modulation by ROS-based nanomedicine has gradually become a highly potential therapeutic strategy, the treatment of other pathological abnormalities can also be assisted by the proper regulation of ROS levels to initiate therapeutic effects. Based on the very recent advances uncovering that ROSinvolved biochemical variations can be utilized to mediate the recovery of some specific diseases,741,742 in this section, we will discuss these important discoveries and give implications on future directions of ROS-based nanomedicines in contributing to greater medical advances in this area. The morbidity of myopia has increased worldwide over the past several decades, and it has now become an almost inevitable problem for the vast majority of people.743 Most affected people use spectacles to provide additional refractive error correction, which brings large troubles to their lives. Refractive surgeries have emerged as attractive options for the permanent correction of vision recently. However, these therapeutic approaches are invasive and may compromise corneal structure, restricting their future developments. Recently, Wang et al. proposed a noninvasive strategy for permanent vision correction by taking advantage of laser− cornea interaction (Figure 81).741 This strategy is based on the employment of a femtosecond laser, which can lead to the lowdensity plasma formation and subsequent ROS production within collagenous tissues and thus to facilitation of the oxidation of surrounding proteins and formation of cross-links, finally triggering changes in the refractive power of eyes. Here, ROS generation is a consequence of ionization and dissociation processes. First, multiple photons activate the bound electrons above the bandgap, facilitating the formation of electron−hole pairs. Then, water cation radical H2O+ is generated, which subsequently reacts with a water molecule to generate H3O+ and •OH. At the same time, the excited water molecule also dissociates, generating another •OH. Finally, secondary and tertiary reactions also occur that result in the generation of O2•−, H2O2 and other active species. These generated ROS enable the oxidative modification of tyrosine and the

5. FURTHER DISCUSSIONS ON ROS−MATERIAL INTERACTIONS: BIODEGRADABILITY The above sections are concentrated on how to take advantage of ROS−material interactions to generate, scavenge, or respond to ROS, for eliciting therapeutic effects in biosystems. However, during/after these processes, how do ROS interact with these elaborately fabricated functional materials and impact their morphological, structural, or compositional integrity? This question leads us to further explore ROS−material interactions to investigate the underlying chemical principles of ROSinitiated biodegradability of materials. Thus, in this section, we will focus on recent representative studies to discuss how ROS generated in biological systems (especially enzymatic catalysis) BX


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Figure 82. Biodegradation of carboxylated SWNTs catalyzed by hMPO in neutrophils. (a) Stabilization of the carboxylated ends of SWNTs by arginine (Arg) and tyrosine (Tyr) residues in hMPO. (b) Corresponding space-fill representation of (a). (c) AFM image to confirm the binding of a dimer with an SWNT. Reprinted with permission from ref 752. Copyright 2010 Nature Publishing Group.

graded SWNTs did not initiate any inflammatory response, demonstrating that the improved biodegradability is vitally important to mitigate the pro-inflammatory effects of nanomaterials. This pioneering work first reveals a concrete in vivo pathway that initiates enzymatic ROS generation for subsequent SWNTs biodegradation (i.e., neutrophils-hMPO-HClOSWNTs), further pushing forward the biosafety assessment of inorganic nanomaterials. In addition to SWNTs, 2D inorganic materials have also been extensively investigated to be associated with the in vivo enzymatic biodegradation routes in recent years. Kurapati et al. first reported hMPO-triggered biodegradation of GO sheets in the presence of a low concentration of H2O2.753 In this study, hMPO failed to degrade most aggregated GO samples but succeeded in metabolizing highly dispersed ones, demonstrating the dispersibility of nanomedicines is of great significance for guaranteeing high enzymatic biodegradability and long-term biosafety. In successional research, they further evaluated the stability of hexagonal boron nitride (hBN) nanosheets in the presence of hMPO.754 Significant degradation was observed, indicating that the biodegradation of hBN nanosheets is possible in lungs that contain high levels of hMPO. Moreover, we recently investigated the biodegradability of Nb2C (MXene) nanosheets in the presence of hMPO and H2O2.755 The 2D structure of original Nb2C nanosheets was completely lost during coincubation; thus, an in vivo biodegradation route of Nb2C nanosheets has also been demonstrated, which enables its catalytic disintegration and ultimate excretion after fulfilling their therapeutic functions. However, for other inorganic nanomaterials, the interplay between biological ROS and the biodegradability is still unclear. Although numbers of reports have identified their biodistribution and excretion routes, however, they presented little mechanistic explanation on when, where, and how biological ROS were generated to favor the biodegradation of biomaterials. Therefore, more detailed extensive investigations in this area are necessary, to uncover the underlying in vivo mechanisms of inorganic nanomaterials and their ultimate clinical translation potential. The ever-deeper elucidation of ROS-initiated biodegradation of nanomedicines leads us to consider how to accurately modulate such a ROS-material interaction for the regulation of biodegradability and optimization of therapeutic outcomes. For chemically inert materials, the introduction of redox-active moieties into their framework is a general approach to improve

initiate oxidation and consequent degradation of materials, and how to finely modulate such a ROS−material interaction to control the biodegradation courses for optimization of functionality. The biodegradation of nanomaterials is closely associated with an endogenous immune system because these materials are regarded as extraneous invaders by the biological milieu and supposed to be cleared out.747 Typically, immune cells, such as neutrophils, express oxidant-generating enzymes [e.g., human MPO (hMPO)] for initiating ROS generation and subsequent nanomaterial disintegration.748 Organic nanomaterials have been extensively evidenced with desirable oxidative degradability in biosystems,421 but the relatively high stability of inorganic nanomaterials urges researchers to investigate their interactions with biological ROS (or ROS-generating enzymes) in detail for uncovering the underlying in vivo mechanisms that determine biodegradability. In recent years, human-enzymecatalyzed ROS generation for oxidative biodegradation of inorganic nanomaterials has attracted broad attention from the scientific community, and significant breakthroughs in this area have also evidenced that a few inorganic nanomaterials are capable of being endogenously metabolized under the assistance of biological ROS. Such an emerging research field stems from the initial studies on catalytic degradation of single-walled carbon nanotubes (SWNTs) by nonhuman enzymes.749 Allen et al. conducted mechanistic investigations in 2008 and 2009 on HRP-catalyzed in vitro degradation of both carboxylated and pristine SWNTs. 750,751 Significant degradation of carboxylated SWNTs was visualized, but pristine SWNTs presented no degradation during HRP incubation, demonstrating that carboxylated SWNTs are more competent for biomedical applications. However, HRP is not distributed in the human body, and deeper investigations on the human-enzyme-guided biodegradation of SWNTs are highly desired. Based on the two reports, Kagan et al. first evidenced that carboxylated SWNTs can be degraded by hMPO in neutrophils (Figure 82).752 In the presence of biological H2O2, hMPO generates potent HClO and reactive radical intermediates, thus initiating the catalytic oxidation and subsequent biodegradation of SWNTs. Analogous to the previous reports, molecular modeling in this study also suggested that the interaction between the basic amino acids of hMPO and the carboxyls on the SWNTs localizes the nanotubes at the catalytic sites for biodegradation. More importantly, in vivo experiments manifested that the biodeBY


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Figure 83. Sequestration of ambient ROS by a surface functionalization strategy for improved stability. (a) Spatial Raman peak intensity maps (A1g) for a representative pristine BP sheet (days 1 and 8) and a [1-butyl-3-methylimidazolium (BMIM)][BF4]-treated BP flake for the sequestration of ambient ROS (days 1 and 36). Scale bars, 1 μm. (b) Quenching ability of [BMIM][BF4] toward 1O2, O2•− and •OH. Reprinted with permission from ref 756. Copyright 2017 John Wiley and Sons.

oxidative biodegradability (such as the addition of disulfide bonds into the framework of MONs249). This method has also been widely developed for the design of ROS-triggered CDR nanosystems. Comparatively, for chemically active materials, sequestration of ambient ROS is supposed to protect inner agents from overfast disintegration. Recent advances in surface chemistry have provided feasible tools to confer such a functionality by means of, for example, using a blocking layer to resist ROS attack. Walia et al. first evidenced that sequestration of ROS by surface treatment with antioxidant [1-butyl-3-methylimidazolium (BMIM)][BF4] could improve the chemical stability of BP sheets (Figure 83).756 This mechanistic study inspires investigators to manage biodegradability of nanomaterials by creating antioxidant layers for mediating reaction kinetics of ROS-triggered oxidation of a material matrix. It is noted that, though surface engineering strategies have been extensively reported to be able to prevent overoxidation, most of them fail to provide solid experimental or theoretical evidence for uncovering the altered ROS− material interaction that contributes to the regulation of biodegradability.

visualize the biodistribution of TiO2 and Pt particles in mice.765 Although the hydrodynamic sizes of TiO2 and Pt particles were almost the same, however, their pharmacokinetic behaviors were completely different from each other, indicating that the biodistributions of ROS-based nanomedicines are also closely associated with their compositional characteristics. Lartigue et al. demonstrated that the polymer coating of IONPs controlled their surface reactivity and long-term fate in a biosystem.766 In the lysosomal environment (pH = 4.7), the metabolic rate of PEG-coated IONPs is 1.25 times faster than that of poly(maleic anhydride-alt-1-octadecene)-coated ones, while the released cytotoxic Fe ions from both types of IONPs can be further stored by ferritin. Moreover, Arami and his co-workers further systematically explored the biodistribution and metabolic pathways of administered IONPs (Figure 84).767 They pointed out that the generated ferritin after IONPs degradation could transform to transferrin and be delivered into bone marrow subsequently, in which these Fe-containing molecules could be used for hemoglobin synthesis in RBC circulating throughout the body. Given the extensive application of IONPs in cancer

6. PHARMACOKINETICS AND BIODISTRIBUTION OF ROS-BASED NANOPLATFORMS Great efforts have been made in investigating the pharmacokinetics and biodistribution of ROS-based nanoplatforms. Especially, for several typical ROS-regulating nanomaterials, such as TiO2 nanoparticles, CdSe quantum dots, IONPs, CeO2 nanoparticles, and Pt nanoparticles, systematic evaluations have been conducted to explore their biological behaviors after intravenous/oral administration.757−763 In these reports, the size, composition, surface charge, surface coating, and state of agglomeration of the nanosystems have been evidenced to play significant roles in determining their biodistributions, clearances, and long-term fates. For example, Elgrabli et al. have established a pharmacokinetic model to analyze the time-dependent distribution of TiO2 nanoparticles in several organs.764 They discovered that TiO2 nanoparticles below 25 nm in diameter mainly accumulate in liver, lungs, and spleen after intravenous injection and can be cleared from the body with a half-life of 12.7 days. Abe et al. have first employed X-ray scanning analytical microscopy to

Figure 84. Schematic illustration for the biodistribution and metabolic pathways of administered IONPs. MPS, mononuclear phagocytic system. Reprinted with permission from ref 767. Copyright 2015 Royal Society of Chemistry. BZ


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without the exogenous physical stimuli (e.g., light, US, electricity, etc.), can be generally categorized in nanocatalytic medicine. Such an emerging area provides advanced approaches to regulate the types, locations, and concentrations of ROS in biosystems, which, as we hope, will further contribute to the development of ROS-related biomedical fields. Although substantial advances have been made in ROS science, however, this discipline is still at its early stage. There are still numbers of scientific and/or technological issues remaining to be addressed, aiming for the next leap-forward development of ROS science and ROS therapeutics: (1) A number of nanomaterials with ROS-generating capabilities are capable of initiating cytotoxicity (e.g., phototoxicity, chemotoxicity, etc.),770−778 and such a chemical characteristic has been applied for cancer treatment and antibacterial therapy. However, for in vivo application, it is a double-edged sword. After exerting expected therapeutic functions, the elevated ROS level may also impair ambient normal tissues. Moreover, if the nanomaterials are not degraded, their ROS-generating functions may still exist that will result in sustained oxidative damage. Therefore, how to balance the therapeutic function and side effect of ROSgenerating nanomaterials is important for the optimization of therapeutic outcomes, which needs more careful characterization of the in vivo behavior of ROS and more advanced tools for the safety assessment of nanomaterials.779 ROS-based diagnostic modalities and ROS detection strategies may be beneficial to qualitatively recognize and, more importantly, quantitatively measure the local ROS distribution and redox status, and thus to favor a customized treatment regimen. Numerous reports have concentrated on the in vivo transport, pharmacokinetics, and biodistribution of nanomaterials;780 the consequent variations of ROS concentration and locations are also suggested to be systematically evaluated for a comprehensive view of side effects of catalytic nanomaterials. (2) “It is difficult to make predictions, especially about the future,”781 is a popular quote about the arduous task of predicting advances. Recent progress in computational chemistry has provided applicable tools to predict/ explore chemical reactions by first-principle molecular dynamics simulations, such as density functional approximation (DFA) B3LYP conceived 25 years ago. This significant technological advance greatly favors the investigation of ROS-related reaction mechanisms, i.e., how ROS are generated, depleted on the surface of redox-active nanomaterials, and how ROS interact with biomolecules that influence pathological progression. Until now, most ROS-related biomedical research only focuses on high therapeutic performance of as-administrated nanomaterials but lacks mechanistic analysis on molecular principles of the ROS-involved therapeutic process. The combination of computational chemistry, ROS science, and material chemistry will help, though mostly to a limited extent at present, to uncover the mysterious veil of ROS chemistry in the therapeutic process, as evidenced by several recent research reports on ROS-based nanotherapy.275,327 In addition, the optimistic prediction of ROS-related chemical reaction by computational techniques is also instructive for

CDT, drug delivery, and antibacterial therapy, these elucidations provide solid foundations for evaluating the long-term biological effects of IONPs after these nanosystems have fulfilled their therapeutic functions. Liver is the major organ of mononuclear phagocytic system (MPS), where the located Kupffer cells can quickly phagocytize the nearby nanomedicines from the bloodstream.768 A significant study in 2014 by Graham et al. first uncovered the mechanism for time-course evolution of CeO2 nanoparticles inside liver.769 This work evidences that CeO2 undergoes partial dissolution to release Ce ions, which leads to a second generation of CeO2 nanoparticles of 1−3 nm in diameter in both interior and exterior of the liver. Electron energy-loss spectroscopy (EELS) profiles further indicate that such a nanoparticle regrowth shifts the redox activity of CeO2 to a more reduced state (higher Ce3+ content), thus conferring enhanced ROS-scavenging activity and favoring subsequent antioxidative therapy after these nanoparticles are delivered into brain. It is noted that most of the current ROS-based nanomedicines are constructed by integrating different functional species or components into one single nanosystem, rather than using one pristine nanomaterial for actuating in vivo ROS generation/depletion. Therefore, the biological behaviors of each component and the synergistic effects among different components of ROS-based nanomedicines are supposed to be comprehensively evaluated. For current researches on the design and fabrication of highly efficient ROS-based nanomedicines, only limited biological information, such as hematological and histological data, has been provided at the end of these reports to evidence the biocompatibility of the established nanocomposites. It is expected that more comprehensive biosafety investigations (such assessments on long-term neurotoxicity and systemic inflammatory effects) will be undertaken in the future to guarantee that these fabricated therapeutic nanosystems are biocompatible enough for the ultimate clinical translation.

7. CONCLUSIONS AND OUTLOOK The unique features of ROS in biological systems have been driving researchers to take full advantage of these chemical species for contributing to ever-greater medical advances. Thanks to the remarkable advances in the field of nanotechnology, great varieties of nanomaterials with unique ROS regulation capabilities have been explored to guide temporospatially dynamic behaviors of ROS in biological milieu for biomedical applications, which contributes to the emergence of new-generation advanced therapeutic methodology, i.e., nanomaterial-guided in vivo ROS evolution for therapy. It is noted that most ROS-involved nanotherapies are based on the catalytic reactions triggered by delivered nanomedicines. This distinct feature leads us to integrate the terms of “catalysis” and “medicine” for better elucidation of such a catalytic nature, i.e., nanocatalytic medicine. The delivered nanomaterials are able to lower the energy barriers of ROSrelated reactions similar to the catalysts in chemistry, favoring in vivo ROS regulation for initiating therapeutic effects. Moreover, the exogenous physical stimuli can also induce/ accelerate ROS-related catalytic reactions, by exciting the energy levels of nanomedicines, such as TiO2 nanoparticles, which is similar to the photocatalysis in environmental and energy fields. Therefore, most ROS-involved therapeutic processes catalyzed by the delivered nanomaterials, with/ CA


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been approved by Food and Drug Administration (FDA, the United States) and/or National Medical Products Administration (NMPA, China),795 however, most of them are organic nanosystems, in which only limited types of organic nanocarriers (e.g., liposome, polymer conjugate, polymeric micelle, etc.) have been selected to load specific active pharmaceutical ingredients (e.g., Dox, paclitaxel, cisplatin, siRNA, antigens etc.).796−798 These nanosystems are approved for chemotherapy, gene therapy, or immunotherapy, but the ROS-based therapeutic modalities are not involved.799,800 Moreover, although superparamagnetic IONP has been approved in Europe (NanoTherm, 2010) for glioblastoma treatment; the mechanism is based on the local magnetic hyperthermia ablation rather than catalytic ROS regulation.800 IONP coated with polyglucose sorbitol carboxymethyl ether has also been approved by FDA (Feraheme, 2009) based on the sustained release of Fe2+ for anemia treatment, in which the Fenton chemistry is not used for initiating direct therapeutic effects.796 Very recently, hafnium oxide nanoparticle has been developed in clinical trials (NBTXR3, Phase II/III) for enhancing RT of adult soft tissue sarcoma (NCT01433068), which may be the first example of nanomedicine approved for ROS-based therapy. Nevertheless, for most ROS-based nanomedicines, the laboratory technologies have not been successfully approved or even commercialized. There are several issues that may block the further clinical translation of these nanosystems: (1) The exponential increase of publications claiming the therapeutic successes of diverse ROS-regulating nanosystems may lead to the difficulties in the selection of the optimized platform for starting the subsequent clinical trials. (2) The pleiotropy of ROS in biology makes it vitally important to determine the proper administration doses of ROS-based nanomedicines, for guiding the intracellular ROS toward the therapeutic effects rather than pathological ones. (3) Given the current trend in nanomedicine design shifts to the coloading of several therapeutic agents in one nanosystem for approaching multifunctionality and high ROS-regulating efficiency (such as the establishment of sequential catalytic nanosystems for in vivo ROS evolution), it is hard to investigate the safety and efficacy of each component in biosystems. (4) Preclinical studies only provide ultimate treatment outcomes toward established animal models, but the comprehension of the biological mechanisms by which ROS-based nanomedicines interact with the in vivo environment is still lacking or incomplete. Moreover, the tissue textures and physiological behaviors of experimental animals are much different from those of humans, which necessitates more stringent safety and efficacy evaluations of these nanomedicines before administration into the bodies of patients. These challenges lead us to further consider what efforts we can make in the future to push forward the clinical translation of these new-generation nanomedicines. To meet the everstringent requirement of biomedical applications, our researches should target individual needs after patient stratification for therapy regimen selection. These ROS-based therapeutic nanomedicines, such as cancer nanomedicines, are supposed to be conferred with specific responsivenesses for coping with different tumor subpopulations. For example, exogenously triggered ROS-generating nanosystems (in PDT, SDT, and RT) can be tailored for the focused treatments of skin tumors, while TME-responsive ROS-based nanomedicines (in CDT and CDR) can be fabricated for the systemic

researchers to discover/fabricate new redox-active materials for subsequent biomedical applications, i.e., computations first, followed by experimental realization. On account of the quick emerging of chemoinformatics most recently,782 we believe computational chemistry will make a greater contribution to ROS science especially the exploration of ROS-based therapeutic mechanisms on the molecular level. (3) Entering in the era of “precision medicine”, large numbers of nanomaterials are being elaborately fabricated with unique structures, compositions, and surface functionalities to meet the requirement of individual needs.783,784 Based on the endogenous, automatic, and systemic nature of an innate immune system, immunotherapy can be considered as the most typical personalized cancer therapeutic modality.785 Therefore, here, we further underscore the importance of integrating ROS-based therapeutic modalities with immunotherapy for the optimization of antitumor outcome. Given PDT and RT are capable of initiating immunoregulatory cascades in biosystems, the combination of PDT/RT and immunotherapy will lead to superadditive therapeutic effects that are stronger than any monotherapy or their linear combination. The immunoregulatory potential of other emerging cancer therapeutic modalities, such as SDT and CDT, can also be systematically investigated to explore whether they are competent to favor such a synergy of combined therapy or not, further contributing to the enhancement of antitumor outcomes. (4) The ROS-generating/scavenging capability of materials determines ultimate therapeutic performance. Though great advances have been achieved in nanomaterial design and synthesis in the last two decades, how to overcome the limitations of traditional material systems for further significantly improved redox-regulating capability is still the common focus of all chemists. Although the emergence of inorganic catalytic nanozymes, such as Fe3O4 and CeO2, has greatly benefitted the management of intracellular ROS levels, however, their in vivo catalytic efficiencies are supposed to be further improved on account of the stringent demands of clinical translation for ever-decreased drug dosages. Benefitting from the recent advances of catalytic chemistry, especially heterogeneous single-atom catalysis,786−793 the catalytic efficiencies of materials have been significantly improved, which inspires us to take advantage of such an emerging atomic catalytic modality for favoring in vivo ROS regulation. A pioneering work by Deng et al. first reported that a single iron site confined in a graphene matrix could significantly facilitate the catalytic decomposition of H2O2 and subsequent oxidation of benzene at room temperature,794 leading to the next wave of interest and enthusiasm of chemists to design atomic catalytic medicine for highly efficient therapeutics. After addressing these issues in nanomedicine design, the last concern for the development of this evolving field is the clinical translation of these elaborately engineered redox-active nanosystems. To what extent have these laboratory advances been translated to the clinic? What bottlenecks are keeping these nanomedicines from entering the clinic? It should be pointed out that, although a small number of nanomedicines, such as Doxil, Abelcet, DaunoXome, etc., have CB


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Figure 85. Challenges and future directions.

Biographies

treatments of deep-seated tumors. Based on this strategy, we can select the optimized platform(s) based on the unique material chemistry of nanomedicines and the types/stages of diseases. In addition, more feasible diagnostic modalities are expected to be developed for real-time monitoring of ROS content in pathological regions of the human body and thus to determine the doses and administration routes of ROS-based nanomedicines for yielding optimal clinical benefits. It is also noted that, our nanomedicine design should be simplified to enable translational feasibility, rather than decorating sophisticated structures that may render potential biosafety issues. To further accelerate clinical applications, in-depth mechanistic investigations on the long-term biological effects of ROS-based nanomedicines are supposed to be undertaken in animals and humans, and closer cooperation among universities, hospitals, and pharmaceutical companies are also suggested to translate preclinical demonstrations into medical advances. As the aforementioned key scientific and technological issues in the development of ROS-based nanomedicines are becoming better addressed (Figure 85), it is highly expected that we will witness the next wave of ROS-based nanomedicines in the next several decades, finally benefiting the health and well-being of humans.

Bowen Yang received his bachelor’s degree from East China University of Science and Technology (ECUST) in July 2017. He is now a doctoral candidate in Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS), under the supervision of Prof. Yu Chen and Prof. Jianlin Shi. His research focus is on the design, synthesis, and bioapplications of 2D nanomaterials. Yu Chen received his Ph.D. degree at SICCAS. He is now a full professor in SICCAS. His research includes the design, synthesis, and biomedical applications of mesoporous silica/organosilica, 2D biomaterials (graphene, metal oxides, TMDCs, and MXenes), and 3D composite bioimplants, including mesoporous material for drug delivery, molecular nanoprobes for imaging, ultrasound therapy, sonodynamic therapy, cardiac therapy, nonvirus gene delivery vehicles, and in situ localized tumour therapy. He has published more than 150 scientific papers in the nanomedicine field with total citations greater than 10000 times (h-index: 54). Jianlin Shi received his Ph.D. degree in SICCAS in 1989. He is now a full professor of SICCAS. He has been working on advanced ceramic materials for more than ten years, and since 1999 he shifted his research interest to the synthesis of mesoporous materials and mesoporous-based nanocomposites and their catalytic, biomedical, and optical applications. Presently his research interest includes heterogeneous catalysts for energy and environment application, synergetic catalysis, drug delivery, and nanocatalytic medicine. He has published over 500 scientific papers which have been cited more than 31000 times by other scientists with an h-index of 98 (2019). He has been in charge of more than 30 important research projects and has gained a number of awards for his achievements.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Bowen Yang: 0000-0002-8934-0276 Yu Chen: 0000-0002-8206-3325 Jianlin Shi: 0000-0001-8790-195X

ACKNOWLEDGMENTS We greatly acknowledge the financial support from the National Key R&D Program of China (Grant No. 2016YFA0203700), National Natural Science Foundation of

Notes

The authors declare no competing financial interest. CC


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DFT

density functional theory 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl indotriDIR carbocyanine iodide DMPO 5,5-dimethyl-1-pyrroline-N-oxide DMSO dimethyl sulfoxide DOPC 1,2-dioleoyl-sn-glycero-3-phosphocholine DOTAP 1,2-dioleoyl-3-trimethylammonium-propane Dox doxorubicin DPBF 1,3-diphenylisobenzofuran DPPC 1,2-dipalmitoly sn-glycero-3-phosphocholine DSPE-PEG 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)200] ECL electrochemiluminescence ECM extracellular matrix EELS electron energy-loss spectroscopy EMPO 5-(ethoxycarbonyl)-5-methyl-1-pyrroline Noxide EPR enhanced permeability and retention ER endoplasmic reticulum ESR electron spin resonance FBS fetal bovine serum fcc face centered cubic fct face centered tetragonal FDA Food and Drug Administration FITC fluorescein isothiocyanate FL fluorescent FRET Fö rster (fluorescence) resonance energy transfer FTIR Fourier transformation infrared GC glassy carbon GCE glassy carbon electrode GCS glycol chitosan GCSF granulocyte colony-stimulating factor GDP guanosine diphosphate GFP green-fluorescent protein GMCSF granulocyte-macrophage colony-stimulating factor GO graphene oxide GOD glucose oxidase GPC gel permeation chromatography GPX glutathione peroxidase GR reduced graphene oxide; glutathione reductase GRXo oxidized glutaredoxin GRXr reduced glutaredoxin GSH glutathione GSHr reduced glutathione GSSG oxidized glutathione GTP guanosine triphosphate HA hyaluronic acid, hydroxyapatite HAADF-STEM high-angle annular dark field scanning transmission electron microscopy hBN hexagonal boron nitride HE hydroethidine Hf hafnium HFn human heavy-chain ferritin HIFU high intensity focused ultrasound HM hollow microsphere HMME hematoporphyrin monomethyl ether MON mesoporous organosilica nanoparticle MPTS (3-mercaptopropyl) trimethoxysilane HOMO highest occupied molecular orbital HORAC hydroxyl radical antioxidant capacity

China (Grant No. 21835007, 51722211, 51672303), Young Elite Scientist Sponsorship Program by CAST (Grant No. 2015QNRC001), and Program of Shanghai Academic Research Leader (Grant No. 18XD1404300).

ABBREVIATIONS AA L-ascorbic acid Abs antibodies AD Alzheimer’s disease AIE aggregation-induced emission APTES (3-aminopropyl)triethoxysilane ATP adenosine triphosphate BADSC brown adipose-derived stem cell BAP poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] BBB blood−brain barrier BCG bacillus calmette-guerin BHQ black hole quencher BiOI bismuth oxyiodide BMDM bone marrow-derived macrophages BMIM 1-butyl-3-methylimidazolium BMPO 5-tert-butoxycarbonyl-5-methyl-1-pyrroline Noxide BP black phosphorus BPD benzoporphyrin derivative BS bulk solution BSA bovine serum albumin BTES bis[3-(triethoxysilyl)propyl]tetrasulfide C3a - C5a complement component 3a and 5a receptor CARN cascade amplification release nanoparticle CAT catalase CDR controlled drug release CDT chemodynamic therapy Ce6 chlorin e6 CFN copper ferrite nanospheres ChIP-seq chromatin immunoprecipitation followed by sequencing Chla chlorophyll a cisplatin cis-diamminedichloroplatinum CKO conditional knockout CLP cecal ligation and puncture CP conjugated polymer CPH 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine CR Cerenkov radiation CRT calreticulin CTAC cetyltrimethylammonium chloride CTL cytotoxic CD8+ T lymphocyte CTLA-4 cytotoxic T-lymphocyte-associated protein 4 CYPMPO 5-(2,2-dimethyl-1,3-propoxycyclophosphoryl)-5-methyl-1-pyrroline N-oxide Cys cysteine Cyt cytochrome D-1MT dextro-1-methyl tryptophan DAPI 4′,6-diamidino-2-phenylindole DBP 5,15-di(p-benzoato)porphyrin DC dendritic cell DCF 2′,7′-dichlorofluorescein DCFH-DA 2′,7′-dichlorofluorescein diacetate DDI doubly distilled DEPMPO 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide DFA density functional approximation CD


Chemical Reviews HP HPLC HRTEM HRP HSA IBD ICB ICG IDO IDOi IFN-γ IL IL-4 pDNA IONP ISC keV KPN LAD-O LAHP Lapa LCST LDH LED LIFU LPS LRET LRP luminol LUMO MB MCC MCN MCWE MDR Me MeV MHC Mito-ETC MNP MnPpIX MOF MOL MPO MPS MRI MSC MSN MTO MyD88 NAC NF-κB NIR NMP NMPA NOX N-PCNS NQO1 NR NR2B9C OA

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OEG OER OPV ORR P2RX7 PA PARP PB PBAP PBS PD PDT PEG PEG-b-PCL PEG-PMAN

hematoporphyrin high-performance liquid chromatography high-resolution transmission electron microscopy horseradish peroxidase human serum albumin inflammatory bowel disease immune checkpoint blockade indocyanine green indoleamine-2,3-dioxygenase indoleamine 2,3-dioxygenase inhibitor interferon gamma interleukin interleukin-4 plasmid DNA iron oxide nanoparticle intersystem crossing kiloelectronvolt Klebsiella pneumoniae left anterior descending artery occlusion linoleic acid hydroperoxide β-lapachone lower critical solution temperature layered double hydroxide light-emitting diode low intensity-focused US lipopolysaccharide luminescence resonance energy transfer lipoprotein receptor-related protein 5-amino-2,3-dihydro-1,4-phthalazinedione lowest unoccupied molecular orbital methylene blue mesoporous calcium carbonate mesoporous carbon nanosphere mycobacterial cell-wall extract multidrug resistance L-methionine megaelectronvolt major histocompatibility complex mitochondrial electron transport chain 2-methyl-2-nitrosopropane; magnetic nanoparticle manganese-ions-chelated protoporphyrin metal−organic-framework metal−organic layer myeloperoxidase mononuclear phagocytic system magnetic resonance imaging mesenchymal stem cell mesoporous silica nanoparticle mitoxantrone myeloid differentiation primary response gene 88 N-acetylcysteine nuclear factor-kappa B near-infrared light N-methylpyrrolidone National Medical Products Administration NADPH oxidase nitrogen-doped porous carbon nanosphere NADPH:quinone oxidoreductase-1 nanoreactor lys-leu-ser-ser-ileglu-ser-asp-val osteoarthritis

PEI PET Phox PIC PLGA PLNP PMA PMCS PMIL POM PPADT PPa-PEG PpIX PS PTEN PTSA PTT PVA PVP RAP RBC ROS RT S. aureus SAED SAO SBC SBU SCNP SDT SH SHNP siRNA SN38 SNO SOA SOD SOH SOSG SPCD SPN SWNT TAA TBP TCR CE

oligo(ethylene glycol) oxygen evolution reaction oligo(p-phenylenevinylene) oxygen reduction reaction purinogenic receptor photoacoustic poly(ADP-ribose) polymerase Prussian blue phenylboronic acid pinacol ester phosphate buffer solution Parkinson’s disease photodynamic therapy polyethylene glycol poly(ethylene glycol)-b-poly(ε-caprolactone) poly(ethylene glycol)-poly[2(methylacryloyl)ethylnicotinate] polyethylenimine positron emission tomography phagocyte oxidase polyion complex poly(lactic-co-glycolic acid) persistent luminescence nanoparticle phorbol myristate acetate porphyrin-like metal centers photoactivable multi-inhibitor nanoliposome polyoxometalates poly(1,4-phenyleneacetone dimethylene thioketal) PEGylated pyropheophorbide-a protoporphyrin photosensitizer phosphatase and tensin homologue deleted on chromosome 10 p-toluene sulfonic acid photothermal therapy polyvinyl alcohol polyvinylpyrrolidone rapamycin red blood cell reactive oxygen species radiation therapy, radiotherapy Staphylococcus aureus selected area electron diffraction SrAl2O4:Eu2+ sodium bicarbonate secondary building units scintillating nanoparticle sonodynamic therapy thiol semiconductor heterojunction nanoparticle small interfering RNA 7-ethyl-10-hydroxyl-camptothecin S-nitrosothiol secondary organic aerosol superoxide dismutase sulphenic acid singlet oxygen sensor green silicon phthalocyanine dihydroxide semiconducting polymer nanoparticle single-walled carbon nanotube thioacetamide 5,10,15,20-tetra(p-benzoato)porphyrin T cell receptor DOI: 10.1021/acs.chemrev.8b00626 Chem. Rev. XXXX, XXX, XXX−XXX

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(14) Rohrer, F.; Berresheim, H. Strong Correlation between Levels of Tropospheric Hydroxyl Radicals and Solar Ultraviolet Radiation. Nature 2006, 442, 184−187. (15) Fujishima, A.; Honda, K. Electrochemical Photolysis of Water at a Semiconductor Electrode. Nature 1972, 238, 37−38. (16) Nosaka, Y.; Nosaka, A. Understanding Hydroxyl Radical (•OH) Generation Processes in Photocatalysis. ACS Energy Lett. 2016, 1, 356−359. (17) Huo, M.; Wang, L.; Chen, Y.; Shi, J. Tumor-Selective Catalytic Nanomedicine by Nanocatalyst Delivery. Nat. Commun. 2017, 8, 357. (18) Sabharwal, S. S.; Schumacker, P. T. Mitochondrial ROS in Cancer: Initiators, Amplifiers or an Achilles’ Heel? Nat. Rev. Cancer 2014, 14, 709−721. (19) Block, K.; Gorin, Y. Aiding and Abetting Roles of NOX Oxidases in Cellular Transformation. Nat. Rev. Cancer 2012, 12, 627− 637. (20) Lambeth, J. D. NOX Enzymes and the Biology of Reactive Oxygen. Nat. Rev. Immunol. 2004, 4, 181−189. (21) Dickinson, B. C.; Chang, C. J. Chemistry and Biology of Reactive Oxygen Species in Signaling or Stress Responses. Nat. Chem. Biol. 2011, 7, 504−511. (22) Winterbourn, C. C. Reconciling the Chemistry and Biology of Reactive Oxygen Species. Nat. Chem. Biol. 2008, 4, 278−286. (23) Bachi, A.; Dalle-Donne, I.; Scaloni, A. Redox Proteomics: Chemical Principles, Methodological Approaches and Biological/ Biomedical Promises. Chem. Rev. 2013, 113, 596−698. (24) Gardner, P. R.; Fridovich, I. Superoxide Sensitivity of the Escherichia Coli Aconitase. J. Biol. Chem. 1991, 266, 19328−19333. (25) Imlay, J. A. Pathways of Oxidative Damage. Annu. Rev. Microbiol. 2003, 57, 395−418. (26) Toledano, M. B.; Kullik, I.; Trinh, F.; Baird, P. T.; Schneider, T. D.; Storz, G. Redox-Dependent Shift of Oxyr-DNA Contacts Along an Extended DNA-Binding Site: A Mechanism for Differential Promoter Selection. Cell 1994, 78, 897−909. (27) Warburg, O. Beobachtungen Uber Die Oxydationsprozesse Im Seeigelei. Hoppe-Seyler's Z. Physiol. Chem. 1908, 57, 1−16. (28) Holmstrom, K. M.; Finkel, T. Cellular Mechanisms and Physiological Consequences of Redox-Dependent Signalling. Nat. Rev. Mol. Cell Biol. 2014, 15, 411−421. (29) Foreman, J.; Demidchik, V.; Bothwell, J. H.; Mylona, P.; Miedema, H.; Torres, M. A.; Linstead, P.; Costa, S.; Brownlee, C.; Jones, J. D.; et al. Reactive Oxygen Species Produced by Nadph Oxidase Regulate Plant Cell Growth. Nature 2003, 422, 442−446. (30) Kim, J. S.; Huang, T. Y.; Bokoch, G. M. Reactive Oxygen Species Regulate a Slingshot-Cofilin Activation Pathway. Mol. Biol. Cell 2009, 20, 2650−2660. (31) Niethammer, P.; Grabher, C.; Look, A. T.; Mitchison, T. J. A Tissue-Scale Gradient of Hydrogen Peroxide Mediates Rapid Wound Detection in Zebrafish. Nature 2009, 459, 996−999. (32) O’Neill, J. S.; Reddy, A. B. Circadian Clocks in Human Red Blood Cells. Nature 2011, 469, 498−503. (33) Wilson, W. R.; Hay, M. P. Targeting Hypoxia in Cancer Therapy. Nat. Rev. Cancer 2011, 11, 393−410. (34) Denko, N. C. Hypoxia, Hif1 and Glucose Metabolism in the Solid Tumour. Nat. Rev. Cancer 2008, 8, 705−713. (35) Nakazawa, M. S.; Keith, B.; Simon, M. C. Oxygen Availability and Metabolic Adaptations. Nat. Rev. Cancer 2016, 16, 663−673. (36) Jones, R. G.; Thompson, C. B. Tumor Suppressors and Cell Metabolism: A Recipe for Cancer Growth. Genes Dev. 2009, 23, 537− 548. (37) Kincaid, M. M.; Cooper, A. A. Eradicate Er Stress or Die Trying. Antioxid. Redox Signaling 2007, 9, 2373−2387. (38) Finkel, T.; Holbrook, N. J. Oxidants, Oxidative Stress and the Biology of Ageing. Nature 2000, 408, 239−247. (39) Li, W.; Kong, A. N. Molecular Mechanisms of Nrf2-Mediated Antioxidant Response. Mol. Carcinog. 2009, 48, 91−104. (40) Meister, A. Glutathione Deficiency Produced by Inhibition of Its Synthesis, and Its Reversal; Applications in Research and Therapy. Pharmacol. Ther. 1991, 51, 155−194.

triethanolamine transmission electron microscopy 2,2,6,6-tetramethylpiperidine tetraethyl orthosilicate thioketal nanoparticles poly(thioketal phosphoester) toll-like receptor 3,3′,5,5′-tetramethyl-benzidine tumor microenvironment tumor-necrosis factor-α two-photon absorption Tempol triphenylphosphonium temperature-programmed reduction tirapazamine oxidized thioredoxin reduced thioredoxin N1-(4-boronobenzyl)-N3-(4-boronophenyl)N1,N1,N3,N3-tetramethylpropane-1,3-diaminium upconversion nanoparticles ultrasound vascular endothelial growth factor vanadium haloperoxidase volatile organic compound X-ray excited optical luminescence xanthine oxidase X-ray photoelectron spectroscopy

REFERENCES (1) Lehn, J. M. Supramolecular Chemistry: Concepts and Perspectives; Wiley-VCH: Weinheim, 2005; p 3. (2) D’Autreaux, B.; Toledano, M. B. ROS as Signalling Molecules: Mechanisms That Generate Specificity in ROS Homeostasis. Nat. Rev. Mol. Cell Biol. 2007, 8, 813−824. (3) Nosaka, Y.; Nosaka, A. Y. Generation and Detection of Reactive Oxygen Species in Photocatalysis. Chem. Rev. 2017, 117, 11302− 11336. (4) Hayyan, M.; Hashim, M. A.; AlNashef, I. M. Superoxide Ion: Generation and Chemical Implications. Chem. Rev. 2016, 116, 3029− 3085. (5) Schweitzer, C.; Schmidt, R. Physical Mechanisms of Generation and Deactivation of Singlet Oxygen. Chem. Rev. 2003, 103, 1685− 1757. (6) Lissi, E. A.; Encinas, M. V.; Lemp, E.; Rubio, M. A. Singlet Oxygen O2(1Δg) Bimolecular Processes - Solvent and Compartmentalization Effects. Chem. Rev. 1993, 93, 699−723. (7) Gligorovski, S.; Strekowski, R.; Barbati, S.; Vione, D. Environmental Implications of Hydroxyl Radicals (•OH). Chem. Rev. 2015, 115, 13051−13092. (8) Kearns, D. R. Physical and Chemical Properties of Singlet Molecular Oxygen. Chem. Rev. 1971, 71, 395−427. (9) Nathan, C.; Cunningham-Bussel, A. Beyond Oxidative Stress: An Immunologist’s Guide to Reactive Oxygen Species. Nat. Rev. Immunol. 2013, 13, 349−361. (10) Trachootham, D.; Alexandre, J.; Huang, P. Targeting Cancer Cells by ROS-Mediated Mechanisms: A Radical Therapeutic Approach? Nat. Rev. Drug Discovery 2009, 8, 579−591. (11) Barnham, K. J.; Masters, C. L.; Bush, A. I. Neurodegenerative Diseases and Oxidative Stress. Nat. Rev. Drug Discovery 2004, 3, 205− 214. (12) Fraisl, P.; Aragones, J.; Carmeliet, P. Inhibition of Oxygen Sensors as a Therapeutic Strategy for Ischaemic and Inflammatory Disease. Nat. Rev. Drug Discovery 2009, 8, 139−152. (13) Fenton, H. J. H. Lxxiii.Oxidation of Tartaric Acid in Presence of Iron. J. Chem. Soc., Trans. 1894, 65, 899−910. CF


Chemical Reviews

Review

(41) Murphy, M. P. Mitochondrial Thiols in Antioxidant Protection and Redox Signaling: Distinct Roles for Glutathionylation and Other Thiol Modifications. Antioxid. Redox Signaling 2012, 16, 476−495. (42) Bouayed, J.; Bohn, T. Exogenous Antioxidants–Double-Edged Swords in Cellular Redox State: Health Beneficial Effects at Physiologic Doses Versus Deleterious Effects at High Doses. Oxid. Med. Cell. Longevity 2010, 3, 228−237. (43) Yan, L. J.; Levine, R. L.; Sohal, R. S. Oxidative Damage During Aging Targets Mitochondrial Aconitase. Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 11168−11172. (44) Larsen, P. L. Aging and Resistance to Oxidative Damage in Caenorhabditis Elegans. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 8905− 8909. (45) Ogg, S.; Paradis, S.; Gottlieb, S.; Patterson, G. I.; Lee, L.; Tissenbaum, H. A.; Ruvkun, G. The Fork Head Transcription Factor Daf-16 Transduces Insulin-Like Metabolic and Longevity Signals in C. Elegans. Nature 1997, 389, 994−999. (46) Ishii, N.; Fujii, M.; Hartman, P. S.; Tsuda, M.; Yasuda, K.; Senoo-Matsuda, N.; Yanase, S.; Ayusawa, D.; Suzuki, K. A Mutation in Succinate Dehydrogenase Cytochrome B Causes Oxidative Stress and Ageing in Nematodes. Nature 1998, 394, 694−697. (47) Serrano, M.; Lin, A. W.; McCurrach, M. E.; Beach, D.; Lowe, S. W. Oncogenic Ras Provokes Premature Cell Senescence Associated with Accumulation of P53 and P16(Ink4a). Cell 1997, 88, 593−602. (48) Abe, J.; Berk, B. C. Reactive Oxygen Species as Mediators of Signal Transduction in Cardiovascular Disease. Trends Cardiovasc. Med. 1998, 8, 59−64. (49) Martensson, J.; Steinherz, R.; Jain, A.; Meister, A. Glutathione Ester Prevents Buthionine Sulfoximine-Induced Cataracts and Lens Epithelial Cell Damage. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 8727− 8731. (50) Lafon-Cazal, M.; Pietri, S.; Culcasi, M.; Bockaert, J. NmdaDependent Superoxide Production and Neurotoxicity. Nature 1993, 364, 535−537. (51) Wojcicki, J.; Rozewicka, L.; Barcew-Wiszniewska, B.; Samochowiec, L.; Juiwiak, S.; Kadlubowska, D.; Tustanowski, S.; Juzyszyn, Z. Effect of Selenium and Vitamin E on the Development of Experimental Atherosclerosis in Rabbits. Atherosclerosis 1991, 87, 9− 16. (52) Lotharius, J.; Brundin, P. Pathogenesis of Parkinson’s Disease: Dopamine, Vesicles and Alpha-Synuclein. Nat. Rev. Neurosci. 2002, 3, 932−942. (53) Obata, F.; Fons, C. O.; Gould, A. P. Early-Life Exposure to LowDose Oxidants Can Increase Longevity Via Microbiome Remodelling in Drosophila. Nat. Commun. 2018, 9, 975. (54) Sullivan, L. B.; Gui, D. Y.; Vander Heiden, M. G. Altered Metabolite Levels in Cancer: Implications for Tumour Biology and Cancer Therapy. Nat. Rev. Cancer 2016, 16, 680−693. (55) Oberley, L. W. Free Radicals and Diabetes. Free Radical Biol. Med. 1988, 5, 113−124. (56) Gorrini, C.; Harris, I. S.; Mak, T. W. Modulation of Oxidative Stress as an Anticancer Strategy. Nat. Rev. Drug Discovery 2013, 12, 931−947. (57) Chen, E. I.; Hewel, J.; Krueger, J. S.; Tiraby, C.; Weber, M. R.; Kralli, A.; Becker, K.; Yates, J. R., 3rd; Felding-Habermann, B. Adaptation of Energy Metabolism in Breast Cancer Brain Metastases. Cancer Res. 2007, 67, 1472−1486. (58) Miller, T. W.; Isenberg, J. S.; Roberts, D. D. Molecular Regulation of Tumor Angiogenesis and Perfusion Via Redox Signaling. Chem. Rev. 2009, 109, 3099−3124. (59) Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J. ROSGenerating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis. Science 2008, 320, 661−664. (60) Auffan, M.; Rose, J.; Bottero, J. Y.; Lowry, G. V.; Jolivet, J. P.; Wiesner, M. R. Towards a Definition of Inorganic Nanoparticles from an Environmental, Health and Safety Perspective. Nat. Nanotechnol. 2009, 4, 634−641.

(61) Shi, J. On the Synergetic Catalytic Effect in Heterogeneous Nanocomposite Catalysts. Chem. Rev. 2013, 113, 2139−2181. (62) Lin, H.; Chen, Y.; Shi, J. Nanoparticle-Triggered in Situ Catalytic Chemical Reactions for Tumour-Specific Therapy. Chem. Soc. Rev. 2018, 47, 1938−1958. (63) Montemore, M. M.; van Spronsen, M. A.; Madix, R. J.; Friend, C. M. O2 Activation by Metal Surfaces: Implications for Bonding and Reactivity on Heterogeneous Catalysts. Chem. Rev. 2018, 118, 2816− 2862. (64) Mu, Q.; Jiang, G.; Chen, L.; Zhou, H.; Fourches, D.; Tropsha, A.; Yan, B. Chemical Basis of Interactions between Engineered Nanoparticles and Biological Systems. Chem. Rev. 2014, 114, 7740− 7781. (65) Jiang, W.; Kim, B. Y.; Rutka, J. T.; Chan, W. C. NanoparticleMediated Cellular Response Is Size-Dependent. Nat. Nanotechnol. 2008, 3, 145−150. (66) Barnard, A. S. One-to-One Comparison of Sunscreen Efficacy, Aesthetics and Potential Nanotoxicity. Nat. Nanotechnol. 2010, 5, 271−274. (67) Chauhan, V. P.; Stylianopoulos, T.; Martin, J. D.; Popovic, Z.; Chen, O.; Kamoun, W. S.; Bawendi, M. G.; Fukumura, D.; Jain, R. K. Normalization of Tumour Blood Vessels Improves the Delivery of Nanomedicines in a Size-Dependent Manner. Nat. Nanotechnol. 2012, 7, 383−388. (68) Yang, B. W.; Chen, Y.; Shi, J. L. Material Chemistry of TwoDimensional Inorganic Nanosheets in Cancer Theranostics. Chem. 2018, 4, 1284−1313. (69) Chen, Y.; Chen, H.; Shi, J. In Vivo Bio-Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles. Adv. Mater. 2013, 25, 3144−3176. (70) Qian, X. Q.; Gu, Z.; Chen, Y. Two-Dimensional Black Phosphorus Nanosheets for Theranostic Nanomedicine. Mater. Horiz. 2017, 4, 800−816. (71) Whitesides, G. M. Reinventing Chemistry. Angew. Chem., Int. Ed. 2015, 54, 3196−3209. (72) Iyer, G. Y.; Islam, M. F.; Quastel, J. H. Biochemical Aspects of Phagocytosis. Nature 1961, 192, 535−541. (73) McCord, J. M.; Fridovich, I. Superoxide Dismutase. An Enzymic Function for Erythrocuprein (Hemocuprein). J. Biol. Chem. 1969, 244, 6049−6055. (74) Foerder, C. A.; Klebanoff, S. J.; Shapiro, B. M. Hydrogen Peroxide Production, Chemiluminescence, and the Respiratory Burst of Fertilization: Interrelated Events in Early Sea Urchin Development. Proc. Natl. Acad. Sci. U. S. A. 1978, 75, 3183−3187. (75) Klebanoff, S. J. Oxygen-Metabolism and the Toxic Properties of Phagocytes. Ann. Intern. Med. 1980, 93, 480−489. (76) Royerpokora, B.; Kunkel, L. M.; Monaco, A. P.; Goff, S. C.; Newburger, P. E.; Baehner, R. L.; Cole, F. S.; Curnutte, J. T.; Orkin, S. H. Cloning the Gene for an Inherited Human Disorder - Chronic Granulomatous-Disease - on the Basis of Its Chromosomal Location. Nature 1986, 322, 32−38. (77) Szatrowski, T. P.; Nathan, C. F. Production of Large Amounts of Hydrogen-Peroxide by Human Tumor-Cells. Cancer Res. 1991, 51, 794−798. (78) Raab, O. Uber Die Wirkung Fluoreszierender Stoffe Auf Infusorien. Zeitung Biol. 1990, 39, 524−526. (79) Meyer-Betz, F. Untersuchungen Uber Die Biologische Photodynamische Wirkung Des Hematoporphyrins und Anderer Derivative Des Blut und Galenafarbstoffs. Dtsch Arch. Klin. 1913, 112, 476−503. (80) Rosenthal, I.; Sostaric, J. Z.; Riesz, P. Sonodynamic Therapy–a Review of the Synergistic Effects of Drugs and Ultrasound. Ultrason. Sonochem. 2004, 11, 349−363. (81) Dougherty, T. J.; Kaufman, J. E.; Goldfarb, A.; Weishaupt, K. R.; Boyle, D.; Mittleman, A. Photoradiation Therapy for the Treatment of Malignant Tumors. Cancer Res. 1978, 38, 2628−2635. (82) Dugan, L. L.; Gabrielsen, J. K.; Yu, S. P.; Lin, T. S.; Choi, D. W. Buckminsterfullerenol Free Radical Scavengers Reduce Excitotoxic and Apoptotic Death of Cultured Cortical Neurons. Neurobiol. Dis. 1996, 3, 129−135. CG


Chemical Reviews

Review

(105) Ali, H.; van Lier, J. E. Metal Complexes as Photo- and Radiosensitizers. Chem. Rev. 1999, 99, 2379−2450. (106) Idris, N. M.; Gnanasammandhan, M. K.; Zhang, J.; Ho, P. C.; Mahendran, R.; Zhang, Y. In Vivo Photodynamic Therapy Using Upconversion Nanoparticles as Remote-Controlled Nanotransducers. Nat. Med. 2012, 18, 1580−1585. (107) Rehman, F. U.; Zhao, C.; Jiang, H.; Wang, X. Biomedical Applications of Nano-Titania in Theranostics and Photodynamic Therapy. Biomater. Sci. 2016, 4, 40−54. (108) Zhou, Y.; Han, X.; Jing, X.; Chen, Y. Construction of SilicaBased Micro/Nanoplatforms for Ultrasound Theranostic Biomedicine. Adv. Healthcare Mater. 2017, 6, 1700646. (109) McEwan, C.; Kamila, S.; Owen, J.; Nesbitt, H.; Callan, B.; Borden, M.; Nomikou, N.; Hamoudi, R. A.; Taylor, M. A.; Stride, E.; et al. Combined Sonodynamic and Antimetabolite Therapy for the Improved Treatment of Pancreatic Cancer Using Oxygen Loaded Microbubbles as a Delivery Vehicle. Biomaterials 2016, 80, 20−32. (110) Chen, Y. W.; Liu, T. Y.; Chang, P. H.; Hsu, P. H.; Liu, H. L.; Lin, H. C.; Chen, S. Y. A Theranostic Nrgo@Msn-Ion Nanocarrier Developed to Enhance the Combination Effect of Sonodynamic Therapy and Ultrasound Hyperthermia for Treating Tumor. Nanoscale 2016, 8, 12648−12657. (111) You, D. G.; Deepagan, V. G.; Um, W.; Jeon, S.; Son, S.; Chang, H.; Yoon, H. I.; Cho, Y. W.; Swierczewska, M.; Lee, S.; et al. ROSGenerating TiO2 Nanoparticles for Non-Invasive Sonodynamic Therapy of Cancer. Sci. Rep. 2016, 6, 23200. (112) Wang, X.; Wang, W. P.; Yu, L. D.; Tang, Y.; Cao, J. Y.; Chen, Y. Site-Specific Sonocatalytic Tumor Suppression by Chemically Engineered Single-Crystalline Mesoporous Titanium Dioxide Sonosensitizers. J. Mater. Chem. B 2017, 5, 4579−4586. (113) Ouyang, J.; Deng, L.; Chen, W.; Sheng, J.; Liu, Z.; Wang, L.; Liu, Y. N. Two Dimensional Semiconductors for Ultrasound-Mediated Cancer Therapy: The Case of Black Phosphorus Nanosheets. Chem. Commun. 2018, 54, 2874−2877. (114) Dai, Z.; Liu, S.; Bao, J.; Ju, H. Nanostructured FeS as a Mimic Peroxidase for Biocatalysis and Biosensing. Chem. - Eur. J. 2009, 15, 4321−4326. (115) Dutta, A. K.; Maji, S. K.; Srivastava, D. N.; Mondal, A.; Biswas, P.; Paul, P.; Adhikary, B. Synthesis of FeS and FeSe Nanoparticles from a Single Source Precursor: A Study of Their Photocatalytic Activity, Peroxidase-Like Behavior, and Electrochemical Sensing of H2O2. ACS Appl. Mater. Interfaces 2012, 4, 1919−1927. (116) Shu, Q. W.; Li, C. M.; Gao, P. F.; Gao, M. X.; Huang, C. Z. Porous Hollow CuS Nanospheres with Prominent Peroxidase-Like Activity Prepared in Large Scale by a One-Pot Controllable Hydrothermal Step. RSC Adv. 2015, 5, 17458−17465. (117) Dutta, A. K.; Das, S.; Samanta, S.; Samanta, P. K.; Adhikary, B.; Biswas, P. CuS Nanoparticles as a Mimic Peroxidase for Colorimetric Estimation of Human Blood Glucose Level. Talanta 2013, 107, 361− 367. (118) Andre, R.; Natalio, F.; Humanes, M.; Leppin, J.; Heinze, K.; Wever, R.; Schroder, H. C.; Muller, W. E. G.; Tremel, W. V2O5 Nanowires with an Intrinsic Peroxidase-Like Activity. Adv. Funct. Mater. 2011, 21, 501−509. (119) Salvemini, D.; Riley, D. P.; Cuzzocrea, S. SOD Mimetics Are Coming of Age. Nat. Rev. Drug Discovery 2002, 1, 367−374. (120) Riley, D. P. Functional Mimics of Superoxide Dismutase Enzymes as Therapeutic Agents. Chem. Rev. 1999, 99, 2573−2587. (121) Dong, H. J.; Zhang, C.; Fan, Y. Y.; Zhang, W.; Gu, N.; Zhang, Y. Nanozyme and Their ROS Regulation Effect in Cells. Prog. Biochem. Biophys. 2018, 45, 105−117. (122) Markovic, Z.; Trajkovic, V. Biomedical Potential of the Reactive Oxygen Species Generation and Quenching by Fullerenes (C60). Biomaterials 2008, 29, 3561−3573. (123) Ali, S. S.; Hardt, J. I.; Dugan, L. L. SOD Activity of Carboxyfullerenes Predicts Their Neuroprotective Efficacy: A Structure-Activity Study. Nanomedicine 2008, 4, 283−294. (124) Ali, S. S.; Hardt, J. I.; Quick, K. L.; Kim-Han, J. S.; Erlanger, B. F.; Huang, T. T.; Epstein, C. J.; Dugan, L. L. A Biologically Effective

(83) Manea, F.; Houillon, F. B.; Pasquato, L.; Scrimin, P. Nanozymes: Gold-Nanoparticle-Based Transphosphorylation Catalysts. Angew. Chem., Int. Ed. 2004, 43, 6165−6169. (84) Tarnuzzer, R. W.; Colon, J.; Patil, S.; Seal, S. Vacancy Engineered Ceria Nanostructures for Protection from RadiationInduced Cellular Damage. Nano Lett. 2005, 5, 2573−2577. (85) Gao, L.; Zhuang, J.; Nie, L.; Zhang, J.; Zhang, Y.; Gu, N.; Wang, T.; Feng, J.; Yang, D.; Perrett, S.; et al. Intrinsic Peroxidase-Like Activity of Ferromagnetic Nanoparticles. Nat. Nanotechnol. 2007, 2, 577−583. (86) Glass, S. B.; Gonzalez-Fajardo, L.; Beringhs, A. O.; Lu, X. Redox Potential and ROS-Mediated Nanomedicines for Improving Cancer Therapy. Antioxid. Redox Signaling 2019, 30, 747. (87) Zhou, Z.; Song, J.; Nie, L.; Chen, X. Reactive Oxygen Species Generating Systems Meeting Challenges of Photodynamic Cancer Therapy. Chem. Soc. Rev. 2016, 45, 6597−6626. (88) Sims, C. M.; Hanna, S. K.; Heller, D. A.; Horoszko, C. P.; Johnson, M. E.; Montoro Bustos, A. R.; Reipa, V.; Riley, K. R.; Nelson, B. C. Redox-Active Nanomaterials for Nanomedicine Applications. Nanoscale 2017, 9, 15226−15251. (89) Brown, S. B.; Brown, E. A.; Walker, I. The Present and Future Role of Photodynamic Therapy in Cancer Treatment. Lancet Oncol. 2004, 5, 497−508. (90) Dolmans, D. E.; Fukumura, D.; Jain, R. K. Photodynamic Therapy for Cancer. Nat. Rev. Cancer 2003, 3, 380−387. (91) Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev. 2010, 110, 2795−2838. (92) Qian, X.; Zheng, Y.; Chen, Y. Micro/Nanoparticle-Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation. Adv. Mater. 2016, 28, 8097−8129. (93) Xu, H. Y.; Zhang, X.; Han, R. B.; Yang, P. M.; Ma, H. F.; Song, Y.; Lu, Z. C.; Yin, W. D.; Wu, X. X.; Wang, H. Nanoparticles in Sonodynamic Therapy: State of the Art Review. RSC Adv. 2016, 6, 50697−50705. (94) Tang, H.; Zheng, Y.; Chen, Y. Materials Chemistry of Nanoultrasonic Biomedicine. Adv. Mater. 2017, 29, 1604105. (95) Song, G.; Cheng, L.; Chao, Y.; Yang, K.; Liu, Z. Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therapy. Adv. Mater. 2017, 29, 1700996. (96) Saravanakumar, G.; Kim, J.; Kim, W. J. Reactive-OxygenSpecies-Responsive Drug Delivery Systems: Promises and Challenges. Adv. Sci. 2017, 4, 1600124. (97) Huo, M.; Yuan, J.; Tao, L.; Wei, Y. Redox-Responsive Polymers for Drug Delivery: From Molecular Design to Applications. Polym. Chem. 2014, 5, 1519−1528. (98) Fan, W.; Yung, B.; Huang, P.; Chen, X. Nanotechnology for Multimodal Synergistic Cancer Therapy. Chem. Rev. 2017, 117, 13566−13638. (99) Lovell, J. F.; Liu, T. W.; Chen, J.; Zheng, G. Activatable Photosensitizers for Imaging and Therapy. Chem. Rev. 2010, 110, 2839−2857. (100) Chen, H.; Zhou, X.; Gao, Y.; Zheng, B.; Tang, F.; Huang, J. Recent Progress in Development of New Sonosensitizers for Sonodynamic Cancer Therapy. Drug Discovery Today 2014, 19, 502−509. (101) Lin, Y.; Ren, J.; Qu, X. Catalytically Active Nanomaterials: A Promising Candidate for Artificial Enzymes. Acc. Chem. Res. 2014, 47, 1097−1105. (102) Fang, F. C. Antimicrobial Reactive Oxygen and Nitrogen Species: Concepts and Controversies. Nat. Rev. Microbiol. 2004, 2, 820−832. (103) Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R. K. The Role of Porphyrin Chemistry in Tumor Imaging and Photodynamic Therapy. Chem. Soc. Rev. 2011, 40, 340−362. (104) Zhou, Y.; Liang, X.; Dai, Z. Porphyrin-Loaded Nanoparticles for Cancer Theranostics. Nanoscale 2016, 8, 12394−12405. CH


Chemical Reviews

Review

Fullerene (C60) Derivative with Superoxide Dismutase Mimetic Properties. Free Radical Biol. Med. 2004, 37, 1191−1202. (125) Karakoti, A. S.; Monteiro-Riviere, N. A.; Aggarwal, R.; Davis, J. P.; Narayan, R. J.; Self, W. T.; McGinnis, J.; Seal, S. Nanoceria as Antioxidant: Synthesis and Biomedical Applications. JOM 2008, 60, 33−37. (126) Nelson, B. C.; Johnson, M. E.; Walker, M. L.; Riley, K. R.; Sims, C. M. Antioxidant Cerium Oxide Nanoparticles in Biology and Medicine. Antioxidants 2016, 5, 15. (127) Shcherbakov, A. B.; Ivanov, V. K.; Zholobak, N. M.; Ivanova, O. S.; Krysanov, E. Y.; Baranchikov, A. E.; Spivak, N. Y.; Tretyakov, Y. D. Nanocrystalline Ceria Based MaterialsPerspectives for Biomedical Application. Biophysics 2011, 56, 987−1004. (128) Celardo, I.; Pedersen, J. Z.; Traversa, E.; Ghibelli, L. Pharmacological Potential of Cerium Oxide Nanoparticles. Nanoscale 2011, 3, 1411−1420. (129) Das, S.; Dowding, J. M.; Klump, K. E.; McGinnis, J. F.; Self, W.; Seal, S. Cerium Oxide Nanoparticles: Applications and Prospects in Nanomedicine. Nanomedicine 2013, 8, 1483−1508. (130) Xu, C.; Lin, Y.; Wang, J.; Wu, L.; Wei, W.; Ren, J.; Qu, X. Nanoceria-Triggered Synergetic Drug Release Based on CeO2-Capped Mesoporous Silica Host-Guest Interactions and Switchable Enzymatic Activity and Cellular Effects of CeO2. Adv. Healthcare Mater. 2013, 2, 1591−1599. (131) Li, Y.; He, X.; Yin, J. J.; Ma, Y.; Zhang, P.; Li, J.; Ding, Y.; Zhang, J.; Zhao, Y.; Chai, Z.; et al. Acquired Superoxide-Scavenging Ability of Ceria Nanoparticles. Angew. Chem., Int. Ed. 2015, 54, 1832− 1835. (132) Esch, F.; Fabris, S.; Zhou, L.; Montini, T.; Africh, C.; Fornasiero, P.; Comelli, G.; Rosei, R. Electron Localization Determines Defect Formation on Ceria Substrates. Science 2005, 309, 752−755. (133) Korsvik, C.; Patil, S.; Seal, S.; Self, W. T. Superoxide Dismutase Mimetic Properties Exhibited by Vacancy Engineered Ceria Nanoparticles. Chem. Commun. 2007, 0, 1056−1058. (134) Celardo, I.; De Nicola, M.; Mandoli, C.; Pedersen, J. Z.; Traversa, E.; Ghibelli, L. Ce3+ Ions Determine Redox-Dependent AntiApoptotic Effect of Cerium Oxide Nanoparticles. ACS Nano 2011, 5, 4537−4549. (135) Dowding, J. M.; Das, S.; Kumar, A.; Dosani, T.; McCormack, R.; Gupta, A.; Sayle, T. X.; Sayle, D. C.; von Kalm, L.; Seal, S.; et al. Cellular Interaction and Toxicity Depend on Physicochemical Properties and Surface Modification of Redox-Active Nanomaterials. ACS Nano 2013, 7, 4855−4868. (136) Pirmohamed, T.; Dowding, J. M.; Singh, S.; Wasserman, B.; Heckert, E.; Karakoti, A. S.; King, J. E.; Seal, S.; Self, W. T. Nanoceria Exhibit Redox State-Dependent Catalase Mimetic Activity. Chem. Commun. 2010, 46, 2736−2738. (137) Singh, S.; Dosani, T.; Karakoti, A. S.; Kumar, A.; Seal, S.; Self, W. T. A Phosphate-Dependent Shift in Redox State of Cerium Oxide Nanoparticles and Its Effects on Catalytic Properties. Biomaterials 2011, 32, 6745−6753. (138) Heckert, E. G.; Karakoti, A. S.; Seal, S.; Self, W. T. The Role of Cerium Redox State in the SOD Mimetic Activity of Nanoceria. Biomaterials 2008, 29, 2705−2709. (139) Colon, J.; Herrera, L.; Smith, J.; Patil, S.; Komanski, C.; Kupelian, P.; Seal, S.; Jenkins, D. W.; Baker, C. H. Protection from Radiation-Induced Pneumonitis Using Cerium Oxide Nanoparticles. Nanomedicine 2009, 5, 225−231. (140) Wason, M. S.; Colon, J.; Das, S.; Seal, S.; Turkson, J.; Zhao, J.; Baker, C. H. Sensitization of Pancreatic Cancer Cells to Radiation by Cerium Oxide Nanoparticle-Induced ROS Production. Nanomedicine 2013, 9, 558−569. (141) Chen, J.; Patil, S.; Seal, S.; McGinnis, J. F. Rare Earth Nanoparticles Prevent Retinal Degeneration Induced by Intracellular Peroxides. Nat. Nanotechnol. 2006, 1, 142−150. (142) Silva, G. A. Nanomedicine: Seeing the Benefits of Ceria. Nat. Nanotechnol. 2006, 1, 92−94.

(143) Zhang, W.; Hu, S.; Yin, J. J.; He, W.; Lu, W.; Ma, M.; Gu, N.; Zhang, Y. Prussian Blue Nanoparticles as Multienzyme Mimetics and Reactive Oxygen Species Scavengers. J. Am. Chem. Soc. 2016, 138, 5860−5865. (144) Zhang, L.; Laug, L.; Munchgesang, W.; Pippel, E.; Gosele, U.; Brandsch, M.; Knez, M. Reducing Stress on Cells with ApoferritinEncapsulated Platinum Nanoparticles. Nano Lett. 2010, 10, 219−223. (145) Mu, J. S.; Zhao, X.; Li, J.; Yang, E. C.; Zhao, X. J. Novel Hierarchical Nio Nanoflowers Exhibiting Intrinsic Superoxide Dismutase-Like Activity. J. Mater. Chem. B 2016, 4, 5217−5221. (146) Hawkins, C. L.; Davies, M. J. Detection and Characterisation of Radicals in Biological Materials Using EPR Methodology. Biochim. Biophys. Acta, Gen. Subj. 2014, 1840, 708−721. (147) Davies, M. J. Detection and Characterisation of Radicals Using Electron Paramagnetic Resonance (EPR) Spin Trapping and Related Methods. Methods 2016, 109, 21−30. (148) Chiesa, M.; Giamello, E.; Che, M. EPR Characterization and Reactivity of Surface-Localized Inorganic Radicals and Radical Ions. Chem. Rev. 2010, 110, 1320−1347. (149) Rehorek, D. Spin Trapping of Inorganic Radicals. Chem. Soc. Rev. 1991, 20, 341−353. (150) Suzen, S.; Gurer-Orhan, H.; Saso, L. Detection of Reactive Oxygen and Nitrogen Species by Electron Paramagnetic Resonance (EPR) Technique. Molecules 2017, 22, 181. (151) Kalyanaraman, B.; Karoui, H.; Singh, R. J.; Felix, C. C. Detection of Thiyl Radical Adducts Formed During Hydroxyl Radicaland Peroxynitrite-Mediated Oxidation of Thiols–a High Resolution ESR Spin-Trapping Study at Q-Band (35 GHz). Anal. Biochem. 1996, 241, 75−81. (152) Tordo, P. Spin-Trapping: Recent Developments and Applications; Royal Society of Chemistry: Cambridge, 1998; pp 116−144. (153) Davies, M. Recent Developments in Spin Trapping; Royal Society of Chemistry: Cambridge, 2002; pp 47−73. (154) Chen, X.; Wang, F.; Hyun, J. Y.; Wei, T.; Qiang, J.; Ren, X.; Shin, I.; Yoon, J. Recent Progress in the Development of Fluorescent, Luminescent and Colorimetric Probes for Detection of Reactive Oxygen and Nitrogen Species. Chem. Soc. Rev. 2016, 45, 2976−3016. (155) Burns, J. M.; Cooper, W. J.; Ferry, J. L.; King, D. W.; DiMento, B. P.; McNeill, K.; Miller, C. J.; Miller, W. L.; Peake, B. M.; Rusak, S. A.; et al. Methods for Reactive Oxygen Species (ROS) Detection in Aqueous Environments. Aquat. Sci. 2012, 74, 683−734. (156) Flors, C.; Fryer, M. J.; Waring, J.; Reeder, B.; Bechtold, U.; Mullineaux, P. M.; Nonell, S.; Wilson, M. T.; Baker, N. R. Imaging the Production of Singlet Oxygen in Vivo Using a New Fluorescent Sensor, Singlet Oxygen Sensor Green. J. Exp. Bot. 2006, 57, 1725− 1734. (157) Gollmer, A.; Arnbjerg, J.; Blaikie, F. H.; Pedersen, B. W.; Breitenbach, T.; Daasbjerg, K.; Glasius, M.; Ogilby, P. R. Singlet Oxygen Sensor Green®: Photochemical Behavior in Solution and in a Mammalian Cell. Photochem. Photobiol. 2011, 87, 671−679. (158) Kruid, J.; Fogel, R.; Limson, J. L. Quantitative Methylene Blue Decolourisation Assays as Rapid Screening Tools for Assessing the Efficiency of Catalytic Reactions. Chemosphere 2017, 175, 247−252. (159) Moore, C. M.; Pendse, D.; Emberton, M. Photodynamic Therapy for Prostate Cancer–a Review of Current Status and Future Promise. Nat. Clin. Pract. Urol. 2009, 6, 18−30. (160) Castano, A. P.; Mroz, P.; Hamblin, M. R. Photodynamic Therapy and Anti-Tumour Immunity. Nat. Rev. Cancer 2006, 6, 535− 545. (161) Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; et al. Photodynamic Therapy of Cancer: An Update. CaCancer J. Clin. 2011, 61, 250−281. (162) Fan, W.; Huang, P.; Chen, X. Overcoming the Achilles’ Heel of Photodynamic Therapy. Chem. Soc. Rev. 2016, 45, 6488−6519. (163) Ng, K. K.; Lovell, J. F.; Vedadi, A.; Hajian, T.; Zheng, G. SelfAssembled Porphyrin Nanodiscs with Structure-Dependent Activation for Phototherapy and Photodiagnostic Applications. ACS Nano 2013, 7, 3484−3490. CI


Chemical Reviews

Review

Vivo Photodynamic Therapy Via Mitochondria-Involved Apoptosis Pathway. ACS Nano 2015, 9, 2584−2599. (183) Yang, G. X.; Yang, D.; Yang, P. P.; Lv, R. C.; Li, C. X.; Zhong, C. N.; He, F.; Gai, S. L.; Lin, J. A Single 808 nm near-Infrared LightMediated Multiple Imaging and Photodynamic Therapy Based on Titania Coupled Upconversion Nanoparticles. Chem. Mater. 2015, 27, 7957−7968. (184) Gu, B.; Wu, W.; Xu, G.; Feng, G.; Yin, F.; Chong, P. H. J.; Qu, J.; Yong, K. T.; Liu, B. Precise Two-Photon Photodynamic Therapy Using an Efficient Photosensitizer with Aggregation-Induced Emission Characteristics. Adv. Mater. 2017, 29, 1701076. (185) Mauriello Jimenez, C.; Aggad, D.; Croissant, J. G.; Tresfield, K.; Laurencin, D.; Berthomieu, D.; Cubedo, N.; Rossel, M.; Alsaiari, S.; Anjum, D. H.; et al. Porous Porphyrin-Based Organosilica Nanoparticles for NIR Two-Photon Photodynamic Therapy and Gene Delivery in Zebrafish. Adv. Funct. Mater. 2018, 28, 1800235. (186) Cao, H.; Wang, L.; Yang, Y.; Li, J.; Qi, Y.; Li, Y.; Li, Y.; Wang, H.; Li, J. An Assembled Nanocomplex for Improving Both Therapeutic Efficiency and Treatment Depth in Photodynamic Therapy. Angew. Chem., Int. Ed. 2018, 57, 7759−7763. (187) Sakdinawat, A.; Attwood, D. Nanoscale X-Ray Imaging. Nat. Photonics 2010, 4, 840−848. (188) Takahashi, J.; Misawa, M. Characterization of Reactive Oxygen Species Generated by Protoporphyrin IX under X-Ray Irradiation. Radiat. Phys. Chem. 2009, 78, 889−898. (189) Kascakova, S.; Giuliani, A.; Lacerda, S.; Pallier, A.; Mercere, P.; Toth, E.; Refregiers, M. X-Ray-Induced Radiophotodynamic Therapy (RPDT) Using Lanthanide Micelles: Beyond Depth Limitations. Nano Res. 2015, 8, 2373−2379. (190) Zou, X.; Yao, M.; Ma, L.; Hossu, M.; Han, X.; Juzenas, P.; Chen, W. X-Ray-Induced Nanoparticle-Based Photodynamic Therapy of Cancer. Nanomedicine 2014, 9, 2339−2351. (191) Kamkaew, A.; Chen, F.; Zhan, Y.; Majewski, R. L.; Cai, W. Scintillating Nanoparticles as Energy Mediators for Enhanced Photodynamic Therapy. ACS Nano 2016, 10, 3918−3935. (192) Chen, H.; Wang, G. D.; Chuang, Y. J.; Zhen, Z.; Chen, X.; Biddinger, P.; Hao, Z.; Liu, F.; Shen, B.; Pan, Z.; et al. NanoscintillatorMediated X-Ray Inducible Photodynamic Therapy for in Vivo Cancer Treatment. Nano Lett. 2015, 15, 2249−2256. (193) Tang, Y.; Hu, J.; Elmenoufy, A. H.; Yang, X. Highly Efficient FRET System Capable of Deep Photodynamic Therapy Established on X-Ray Excited Mesoporous Laf3:Tb Scintillating Nanoparticles. ACS Appl. Mater. Interfaces 2015, 7, 12261−12269. (194) Lan, G.; Ni, K.; Xu, R.; Lu, K.; Lin, Z.; Chan, C.; Lin, W. Nanoscale Metal-Organic Layers for Deeply Penetrating X-RayInduced Photodynamic Therapy. Angew. Chem., Int. Ed. 2017, 56, 12102−12106. (195) Zhao, M.; Huang, Y.; Peng, Y.; Huang, Z.; Ma, Q.; Zhang, H. Two-Dimensional Metal-Organic Framework Nanosheets: Synthesis and Applications. Chem. Soc. Rev. 2018, 47, 6267−6295. (196) Ma, L.; Zou, X. J.; Bui, B.; Chen, W.; Song, K. H.; Solberg, T. X-Ray Excited ZnS:Cu,Co Afterglow Nanoparticles for Photodynamic Activation. Appl. Phys. Lett. 2014, 105,013702. (197) Song, L.; Li, P. P.; Yang, W.; Lin, X. H.; Liang, H.; Chen, X. F.; Liu, G.; Li, J.; Yang, H. H. Low-Dose X-Ray Activation of W(VI)Doped Persistent Luminescence Nanoparticles for Deep-Tissue Photodynamic Therapy. Adv. Funct. Mater. 2018, 28, 1707496. (198) Fan, W.; Lu, N.; Xu, C.; Liu, Y.; Lin, J.; Wang, S.; Shen, Z.; Yang, Z.; Qu, J.; Wang, T.; et al. Enhanced Afterglow Performance of Persistent Luminescence Implants for Efficient Repeatable Photodynamic Therapy. ACS Nano 2017, 11, 5864−5872. (199) Pratt, E. C.; Shaffer, T. M.; Zhang, Q.; Drain, C. M.; Grimm, J. Nanoparticles as Multimodal Photon Transducers of Ionizing Radiation. Nat. Nanotechnol. 2018, 13, 418−426. (200) Kamkaew, A.; Cheng, L.; Goel, S.; Valdovinos, H. F.; Barnhart, T. E.; Liu, Z.; Cai, W. Cerenkov Radiation Induced Photodynamic Therapy Using Chlorin e6-Loaded Hollow Mesoporous Silica Nanoparticles. ACS Appl. Mater. Interfaces 2016, 8, 26630−26637.

(164) Li, Y.; Lin, T. Y.; Luo, Y.; Liu, Q.; Xiao, W.; Guo, W.; Lac, D.; Zhang, H.; Feng, C.; Wachsmann-Hogiu, S.; et al. A Smart and Versatile Theranostic Nanomedicine Platform Based on Nanoporphyrin. Nat. Commun. 2014, 5, 4712. (165) Tsay, J. M.; Trzoss, M.; Shi, L.; Kong, X.; Selke, M.; Jung, M. E.; Weiss, S. Singlet Oxygen Production by Peptide-Coated Quantum Dot-Photosensitizer Conjugates. J. Am. Chem. Soc. 2007, 129, 6865− 6871. (166) Rozhkova, E. A.; Ulasov, I.; Lai, B.; Dimitrijevic, N. M.; Lesniak, M. S.; Rajh, T. A High-Performance Nanobio Photocatalyst for Targeted Brain Cancer Therapy. Nano Lett. 2009, 9, 3337−3342. (167) Thompson, T. L.; Yates, J. T., Jr. Surface Science Studies of the Photoactivation of TiO2–New Photochemical Processes. Chem. Rev. 2006, 106, 4428−4453. (168) Kovalev, D.; Fujii, M. Silicon Nanocrystals: Photosensitizers for Oxygen Molecules. Adv. Mater. 2005, 17, 2531−2544. (169) Xiao, L.; Gu, L.; Howell, S. B.; Sailor, M. J. Porous Silicon Nanoparticle Photosensitizers for Singlet Oxygen and Their Phototoxicity against Cancer Cells. ACS Nano 2011, 5, 3651−3659. (170) Seidl, C.; Ungelenk, J.; Zittel, E.; Bergfeldt, T.; Sleeman, J. P.; Schepers, U.; Feldmann, C. Tin Tungstate Nanoparticles: A Photosensitizer for Photodynamic Tumor Therapy. ACS Nano 2016, 10, 3149−3157. (171) Zhang, M.; Cui, Z.; Song, R.; Lv, B.; Tang, Z.; Meng, X.; Chen, X.; Zheng, X.; Zhang, J.; Yao, Z.; et al. SnWO4-Based Nanohybrids with Full Energy Transfer for Largely Enhanced Photodynamic Therapy and Radiotherapy. Biomaterials 2018, 155, 135−144. (172) Samia, A. C.; Chen, X.; Burda, C. Semiconductor Quantum Dots for Photodynamic Therapy. J. Am. Chem. Soc. 2003, 125, 15736− 15737. (173) Li, X.-B.; Tung, C.-H.; Wu, L.-Z. Semiconducting Quantum Dots For artificial Photosynthesis. Nat. Rev. Chem. 2018, 2, 160−173. (174) Ge, J.; Lan, M.; Zhou, B.; Liu, W.; Guo, L.; Wang, H.; Jia, Q.; Niu, G.; Huang, X.; Zhou, H.; et al. A Graphene Quantum Dot Photodynamic Therapy Agent with High Singlet Oxygen Generation. Nat. Commun. 2014, 5, 4596. (175) Markovic, Z. M.; Ristic, B. Z.; Arsikin, K. M.; Klisic, D. G.; Harhaji-Trajkovic, L. M.; Todorovic-Markovic, B. M.; Kepic, D. P.; Kravic-Stevovic, T. K.; Jovanovic, S. P.; Milenkovic, M. M.; et al. Graphene Quantum Dots as Autophagy-Inducing Photodynamic Agents. Biomaterials 2012, 33, 7084−7092. (176) Chen, H.; Qiu, Y.; Ding, D.; Lin, H.; Sun, W.; Wang, G. D.; Huang, W.; Zhang, W.; Lee, D.; Liu, G.; et al. GadoliniumEncapsulated Graphene Carbon Nanotheranostics for Imaging-Guided Photodynamic Therapy. Adv. Mater. 2018, 30, 1802748. (177) Zhang, D.; Wen, L.; Huang, R.; Wang, H.; Hu, X.; Xing, D. Mitochondrial Specific Photodynamic Therapy by Rare-Earth Nanoparticles Mediated near-Infrared Graphene Quantum Dots. Biomaterials 2018, 153, 14−26. (178) Wang, H.; Yang, X.; Shao, W.; Chen, S.; Xie, J.; Zhang, X.; Wang, J.; Xie, Y. Ultrathin Black Phosphorus Nanosheets for Efficient Singlet Oxygen Generation. J. Am. Chem. Soc. 2015, 137, 11376− 11382. (179) Xu, Y.; Shi, Z.; Zhang, L.; Brown, E. M.; Wu, A. Layered Bismuth Oxyhalide Nanomaterials for Highly Efficient Tumor Photodynamic Therapy. Nanoscale 2016, 8, 12715−12722. (180) Liu, Y.; Liu, Y.; Bu, W.; Cheng, C.; Zuo, C.; Xiao, Q.; Sun, Y.; Ni, D.; Zhang, C.; Liu, J.; et al. Hypoxia Induced by UpconversionBased Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors. Angew. Chem., Int. Ed. 2015, 54, 8105−8109. (181) Yu, Z.; Sun, Q.; Pan, W.; Li, N.; Tang, B. A near-Infrared Triggered Nanophotosensitizer Inducing Domino Effect on Mitochondrial Reactive Oxygen Species Burst for Cancer Therapy. ACS Nano 2015, 9, 11064−11074. (182) Hou, Z.; Zhang, Y.; Deng, K.; Chen, Y.; Li, X.; Deng, X.; Cheng, Z.; Lian, H.; Li, C.; Lin, J. UV-Emitting Upconversion-Based TiO2 Photosensitizing Nanoplatform: Near-Infrared Light Mediated in CJ


Chemical Reviews

Review

(201) Kotagiri, N.; Sudlow, G. P.; Akers, W. J.; Achilefu, S. Breaking the Depth Dependency of Phototherapy with Cerenkov Radiation and Low-Radiance-Responsive Nanophotosensitizers. Nat. Nanotechnol. 2015, 10, 370−379. (202) Durantini, A. M.; Greene, L. E.; Lincoln, R.; Martinez, S. R.; Cosa, G. Reactive Oxygen Species Mediated Activation of a Dormant Singlet Oxygen Photosensitizer: From Autocatalytic Singlet Oxygen Amplification to Chemicontrolled Photodynamic Therapy. J. Am. Chem. Soc. 2016, 138, 1215−1225. (203) Ai, X.; Ho, C. J.; Aw, J.; Attia, A. B.; Mu, J.; Wang, Y.; Wang, X.; Wang, Y.; Liu, X.; Chen, H.; et al. In Vivo Covalent Cross-Linking of Photon-Converted Rare-Earth Nanostructures for Tumour Localization and Theranostics. Nat. Commun. 2016, 7, 10432. (204) Mu, J.; Lin, J.; Huang, P.; Chen, X. Development of Endogenous Enzyme-Responsive Nanomaterials for Theranostics. Chem. Soc. Rev. 2018, 47, 5554−5573. (205) Pan, L. M.; Liu, J. A.; Shi, J. L. Intranuclear Photosensitizer Delivery and Photosensitization for Enhanced Photodynamic Therapy with Ultralow Irradiance. Adv. Funct. Mater. 2014, 24, 7318−7327. (206) Pan, L.; Liu, J.; He, Q.; Shi, J. MSN-Mediated Sequential Vascular-to-Cell Nuclear-Targeted Drug Delivery for Efficient Tumor Regression. Adv. Mater. 2014, 26, 6742−6748. (207) Pan, L.; Liu, J.; Shi, J. Cancer Cell Nucleus-Targeting Nanocomposites for Advanced Tumor Therapeutics. Chem. Soc. Rev. 2018, 47, 6930−6946. (208) Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles. J. Am. Chem. Soc. 2012, 134, 5722−5725. (209) Yang, B.; Chen, Y.; Shi, J. Exogenous/Endogenous-Triggered Mesoporous Silica Cancer Nanomedicine. Adv. Healthcare Mater. 2018, 7, 1800268. (210) Li, X.; Kwon, N.; Guo, T.; Liu, Z.; Yoon, J. Innovative Strategies for Hypoxic-Tumor Photodynamic Therapy. Angew. Chem., Int. Ed. 2018, 57, 11522−11531. (211) Li, S. Y.; Cheng, H.; Xie, B. R.; Qiu, W. X.; Zeng, J. Y.; Li, C. X.; Wan, S. S.; Zhang, L.; Liu, W. L.; Zhang, X. Z. Cancer Cell Membrane Camouflaged Cascade Bioreactor for Cancer Targeted Starvation and Photodynamic Therapy. ACS Nano 2017, 11, 7006− 7018. (212) Cheng, H.; Zhu, J. Y.; Li, S. Y.; Zeng, J. Y.; Lei, Q.; Chen, K. W.; Zhang, C.; Zhang, X. Z. An O2 Self-Sufficient Biomimetic Nanoplatform for Highly Specific and Efficient Photodynamic Therapy. Adv. Funct. Mater. 2016, 26, 7847−7860. (213) Zhu, H.; Li, J.; Qi, X.; Chen, P.; Pu, K. Oxygenic Hybrid Semiconducting Nanoparticles for Enhanced Photodynamic Therapy. Nano Lett. 2018, 18, 586−594. (214) Zhang, C.; Chen, W.-H.; Liu, L.-H.; Qiu, W.-X.; Yu, W.-Y.; Zhang, X.-Z. An O2 Self-Supplementing and Reactive-Oxygen-SpeciesCirculating Amplified Nanoplatform Via H2O/H2O2 Splitting for Tumor Imaging and Photodynamic Therapy. Adv. Funct. Mater. 2017, 27, 1700626. (215) Zhu, W.; Dong, Z.; Fu, T.; Liu, J.; Chen, Q.; Li, Y.; Zhu, R.; Xu, L.; Liu, Z. Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 nanoparticles to Enhance Photodynamic Therapy. Adv. Funct. Mater. 2016, 26, 5490−5498. (216) Gao, S.; Wang, G.; Qin, Z.; Wang, X.; Zhao, G.; Ma, Q.; Zhu, L. Oxygen-Generating Hybrid Nanoparticles to Enhance Fluorescent/ Photoacoustic/Ultrasound Imaging Guided Tumor Photodynamic Therapy. Biomaterials 2017, 112, 324−335. (217) Fan, H.; Yan, G.; Zhao, Z.; Hu, X.; Zhang, W.; Liu, H.; Fu, X.; Fu, T.; Zhang, X. B.; Tan, W. A Smart Photosensitizer-Manganese Dioxide Nanosystem for Enhanced Photodynamic Therapy by Reducing Glutathione Levels in Cancer Cells. Angew. Chem., Int. Ed. 2016, 55, 5477−5482. (218) Wang, Z.; Zhang, Y.; Ju, E.; Liu, Z.; Cao, F.; Chen, Z.; Ren, J.; Qu, X. Biomimetic Nanoflowers by Self-Assembly of Nanozymes to Induce Intracellular Oxidative Damage against Hypoxic Tumors. Nat. Commun. 2018, 9, 3334.

(219) Bai, J.; Jia, X.; Zhen, W.; Cheng, W.; Jiang, X. A Facile IonDoping Strategy to Regulate Tumor Microenvironments for Enhanced Multimodal Tumor Theranostics. J. Am. Chem. Soc. 2018, 140, 106− 109. (220) Kim, J.; Cho, H. R.; Jeon, H.; Kim, D.; Song, C.; Lee, N.; Choi, S. H.; Hyeon, T. Continuous O2-Evolving MnFe2O4 NanoparticleAnchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer. J. Am. Chem. Soc. 2017, 139, 10992−10995. (221) Wang, X. S.; Zeng, J. Y.; Zhang, M. K.; Zeng, X.; Zhang, X. Z. A Versatile Pt-Based Core-Shell Nanoplatform as a Nanofactory for Enhanced Tumor Therapy. Adv. Funct. Mater. 2018, 28, 1801783. (222) Wei, J. P.; Li, J. C.; Sun, D.; Li, Q.; Ma, J. Y.; Chen, X. L.; Zhu, X.; Zheng, N. F. A Novel Theranostic Nanoplatform Based on Pd@PtPEG-Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment. Adv. Funct. Mater. 2018, 28, 1706310. (223) Yu, L. D.; Chen, Y.; Chen, H. R. H2O2-Responsive Theranostic Nanomedicine. Chin. Chem. Lett. 2017, 28, 1841−1850. (224) Zheng, D. W.; Li, B.; Li, C. X.; Fan, J. X.; Lei, Q.; Li, C.; Xu, Z.; Zhang, X. Z. Carbon-Dot-Decorated Carbon Nitride Nanoparticles for Enhanced Photodynamic Therapy against Hypoxic Tumor Via Water Splitting. ACS Nano 2016, 10, 8715−8722. (225) Liu, L. H.; Zhang, Y. H.; Qiu, W. X.; Zhang, L.; Gao, F.; Li, B.; Xu, L.; Fan, J. X.; Li, Z. H.; Zhang, X. Z. Dual-Stage Light Amplified Photodynamic Therapy against Hypoxic Tumor Based on an O2 SelfSufficient Nanoplatform. Small 2017, 13, 1701621. (226) Park, S. M.; Aalipour, A.; Vermesh, O.; Yu, J. H.; Gambhir, S. S. Towards Clinically Translatable in Vivo Nanodiagnostics. Nat. Rev. Mater. 2017, 2, 17014. (227) Wang, X.; Chen, H.; Zhang, K.; Ma, M.; Li, F.; Zeng, D.; Zheng, S.; Chen, Y.; Jiang, L.; Xu, H.; et al. An Intelligent Nanotheranostic Agent for Targeting, Redox-Responsive Ultrasound Imaging, and Imaging-Guided High-Intensity Focused Ultrasound Synergistic Therapy. Small 2014, 10, 1403−1411. (228) Wang, X.; Chen, H.; Chen, Y.; Ma, M.; Zhang, K.; Li, F.; Zheng, Y.; Zeng, D.; Wang, Q.; Shi, J. Perfluorohexane-Encapsulated Mesoporous Silica Nanocapsules as Enhancement Agents for Highly Efficient High Intensity Focused Ultrasound (HIFU). Adv. Mater. 2012, 24, 785−791. (229) Chen, Y.; Chen, H.; Shi, J. Nanobiotechnology Promotes Noninvasive High-Intensity Focused Ultrasound Cancer Surgery. Adv. Healthcare Mater. 2015, 4, 158−165. (230) Kennedy, J. E. High-Intensity Focused Ultrasound in the Treatment of Solid Tumours. Nat. Rev. Cancer 2005, 5, 321−327. (231) Rizzitelli, S.; Giustetto, P.; Boffa, C.; Delli Castelli, D.; Cutrin, J. C.; Aime, S.; Terreno, E. In Vivo MRI Visualization of Release from Liposomes Triggered by Local Application of Pulsed Low-Intensity Non-Focused Ultrasound. Nanomedicine 2014, 10, 901−904. (232) Deffieux, T.; Younan, Y.; Wattiez, N.; Tanter, M.; Pouget, P.; Aubry, J. F. Low-Intensity Focused Ultrasound Modulates Monkey Visuomotor Behavior. Curr. Biol. 2013, 23, 2430−2433. (233) Zhang, K.; Xu, H.; Chen, H.; Jia, X.; Zheng, S.; Cai, X.; Wang, R.; Mou, J.; Zheng, Y.; Shi, J. CO2 Bubbling-Based ’Nanobomb’ System for Targetedly Suppressing Panc-1 Pancreatic Tumor Via Low Intensity Ultrasound-Activated Inertial Cavitation. Theranostics 2015, 5, 1291−1302. (234) Zhang, K.; Chen, H.; Li, F.; Wang, Q.; Zheng, S.; Xu, H.; Ma, M.; Jia, X.; Chen, Y.; Mou, J.; et al. A Continuous Tri-Phase Transition Effect for HIFU-Mediated Intravenous Drug Delivery. Biomaterials 2014, 35, 5875−5885. (235) Wang, S. G.; Zhao, J. L.; Hu, F.; Li, X.; An, X. A.; Zhou, S. L.; Chen, Y.; Huang, M. X. Phase-Changeable and Bubble-Releasing Implants for Highly Efficient HIFU-Responsive Tumor Surgery and Chemotherapy. J. Mater. Chem. B 2016, 4, 7368−7378. (236) Ma, M.; Xu, H.; Chen, H.; Jia, X.; Zhang, K.; Wang, Q.; Zheng, S.; Wu, R.; Yao, M.; Cai, X.; et al. A Drug-Perfluorocarbon Nanoemulsion with an Ultrathin Silica Coating for the Synergistic CK


Chemical Reviews

Review

Effect of Chemotherapy and Ablation by High-Intensity Focused Ultrasound. Adv. Mater. 2014, 26, 7378−7385. (237) Mitragotri, S. Healing Sound: The Use of Ultrasound in Drug Delivery and Other Therapeutic Applications. Nat. Rev. Drug Discovery 2005, 4, 255−260. (238) Umemura, S.; Kawabata, K.; Sasaki, K.; Yumita, N.; Umemura, K.; Nishigaki, R. Recent Advances in Sonodynamic Approach to Cancer Therapy. Ultrason. Sonochem. 1996, 3, 187−191. (239) Yumita, N.; Iwase, Y.; Nishi, K.; Komatsu, H.; Takeda, K.; Onodera, K.; Fukai, T.; Ikeda, T.; Umemura, S.; Okudaira, K.; et al. Involvement of Reactive Oxygen Species in Sonodynamically Induced Apoptosis Using a Novel Porphyrin Derivative. Theranostics 2012, 2, 880−888. (240) Lv, Y.; Zheng, J.; Zhou, Q.; Jia, L.; Wang, C.; Liu, N.; Zhao, H.; Ji, H.; Li, B.; Cao, W. Antiproliferative and Apoptosis-Inducing Effect of Exo-Protoporphyrin IX Based Sonodynamic Therapy on Human Oral Squamous Cell Carcinoma. Sci. Rep. 2017, 7, 40967. (241) Gao, Z.; Zheng, J.; Yang, B.; Wang, Z.; Fan, H.; Lv, Y.; Li, H.; Jia, L.; Cao, W. Sonodynamic Therapy Inhibits Angiogenesis and Tumor Growth in a Xenograft Mouse Model. Cancer Lett. 2013, 335, 93−99. (242) Liang, L.; Xie, S.; Jiang, L.; Jin, H.; Li, S.; Liu, J. The Combined Effects of Hematoporphyrin Monomethyl Ether-SDT and Doxorubicin on the Proliferation of QBC939 Cell Lines. Ultrasound Med. Biol. 2013, 39, 146−160. (243) Yoshida, T.; Kondo, T.; Ogawa, R.; Feril, L. B., Jr.; Zhao, Q. L.; Watanabe, A.; Tsukada, K. Combination of Doxorubicin and LowIntensity Ultrasound Causes a Synergistic Enhancement in Cell Killing and an Additive Enhancement in Apoptosis Induction in Human Lymphoma U937 Cells. Cancer Chemother. Pharmacol. 2008, 61, 559− 567. (244) Tsai, W. B.; Lai, H. Y.; Lee, J. L.; Lo, C. W.; Chen, W. S. Enhancement of the Cytotoxicity and Selectivity of Doxorubicin to Hepatoma Cells by Synergistic Combination of Galactose-Decorated Gamma-Poly(Glutamic Acid) Nanoparticles and Low-Intensity Ultrasound. Langmuir 2014, 30, 5510−5517. (245) Chen, G.; Roy, I.; Yang, C.; Prasad, P. N. Nanochemistry and Nanomedicine for Nanoparticle-Based Diagnostics and Therapy. Chem. Rev. 2016, 116, 2826−2885. (246) Huang, P.; Qian, X.; Chen, Y.; Yu, L.; Lin, H.; Wang, L.; Zhu, Y.; Shi, J. Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy. J. Am. Chem. Soc. 2017, 139, 1275−1284. (247) Huang, X.; Groves, J. T. Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins. Chem. Rev. 2018, 118, 2491−2553. (248) Riccardi, L.; Genna, V.; De Vivo, M. Metal-Ligand Interactions in Drug Design. Nat. Rev. Chem. 2018, 2, 100−112. (249) Li, Z. L.; Han, J.; Yu, L. D.; Qian, X. Q.; Xing, H.; Lin, H.; Wu, M. C.; Yang, T.; Chen, Y. Synergistic Sonodynamic/Chemotherapeutic Suppression of Hepatocellular Carcinoma by Targeted Biodegradable Mesoporous Nanosonosensitizers. Adv. Funct. Mater. 2018, 28, 1800145. (250) Liu, J. N.; Bu, W.; Shi, J. Chemical Design and Synthesis of Functionalized Probes for Imaging and Treating Tumor Hypoxia. Chem. Rev. 2017, 117, 6160−6224. (251) McEwan, C.; Owen, J.; Stride, E.; Fowley, C.; Nesbitt, H.; Cochrane, D.; Coussios, C. C.; Borden, M.; Nomikou, N.; McHale, A. P.; et al. Oxygen Carrying Microbubbles for Enhanced Sonodynamic Therapy of Hypoxic Tumours. J. Controlled Release 2015, 203, 51−56. (252) Chen, J.; Luo, H.; Liu, Y.; Zhang, W.; Li, H.; Luo, T.; Zhang, K.; Zhao, Y.; Liu, J. Oxygen-Self-Produced Nanoplatform for Relieving Hypoxia and Breaking Resistance to Sonodynamic Treatment of Pancreatic Cancer. ACS Nano 2017, 11, 12849−12862. (253) Zhu, P.; Chen, Y.; Shi, J. Nanoenzyme-Augmented Cancer Sonodynamic Therapy by Catalytic Tumor Oxygenation. ACS Nano 2018, 12, 3780−3795.

(254) Qian, X.; Han, X.; Chen, Y. Insights into the Unique Functionality of Inorganic Micro/Nanoparticles for Versatile Ultrasound Theranostics. Biomaterials 2017, 142, 13−30. (255) Deepagan, V. G.; You, D. G.; Um, W.; Ko, H.; Kwon, S.; Choi, K. Y.; Yi, G. R.; Lee, J. Y.; Lee, D. S.; Kim, K.; et al. Long-Circulating Au-TiO2 Nanocomposite as a Sonosensitizer for ROS-Mediated Eradication of Cancer. Nano Lett. 2016, 16, 6257−6264. (256) Harada, A.; Ono, M.; Yuba, E.; Kono, K. Titanium Dioxide Nanoparticle-Entrapped Polyion Complex Micelles Generate Singlet Oxygen in the Cells by Ultrasound Irradiation for Sonodynamic Therapy. Biomater. Sci. 2013, 1, 65−73. (257) Lu, Q.; Lu, Z.; Lu, Y.; Lv, L.; Ning, Y.; Yu, H.; Hou, Y.; Yin, Y. Photocatalytic Synthesis and Photovoltaic Application of Ag-TiO2 Nanorod Composites. Nano Lett. 2013, 13, 5698−5702. (258) Wang, Z.; Yang, C. Y.; Lin, T. Q.; Yin, H.; Chen, P.; Wan, D. Y.; Xu, F. F.; Huang, F. Q.; Lin, J. H.; Xie, X. M.; et al. Visible-Light Photocatalytic, Solar Thermal and Photoelectrochemical Properties of Aluminium-Reduced Black Titania. Energy Environ. Sci. 2013, 6, 3007− 3014. (259) Waiskopf, N.; Ben-Shahar, Y.; Banin, U. Photocatalytic Hybrid Semiconductor-Metal Nanoparticles; from Synergistic Properties to Emerging Applications. Adv. Mater. 2018, 30, 1706697. (260) Waiskopf, N.; Ben-Shahar, Y.; Galchenko, M.; Carmel, I.; Moshitzky, G.; Soreq, H.; Banin, U. Photocatalytic Reactive Oxygen Species Formation by Semiconductor-Metal Hybrid Nanoparticles. Toward Light-Induced Modulation of Biological Processes. Nano Lett. 2016, 16, 4266−4273. (261) Dai, C.; Zhang, S.; Liu, Z.; Wu, R.; Chen, Y. Two-Dimensional Graphene Augments Nanosonosensitized Sonocatalytic Tumor Eradication. ACS Nano 2017, 11, 9467−9480. (262) Li, J.; Pei, Q.; Wang, R.; Zhou, Y.; Zhang, Z.; Cao, Q.; Wang, D.; Mi, W.; Du, Y. Enhanced Photocatalytic Performance through Magnetic Field Boosting Carrier Transport. ACS Nano 2018, 12, 3351−3359. (263) Han, X.; Huang, J.; Jing, X.; Yang, D.; Lin, H.; Wang, Z.; Li, P.; Chen, Y. Oxygen-Deficient Black Titania for Synergistic/Enhanced Sonodynamic and Photoinduced Cancer Therapy at near Infrared-II Biowindow. ACS Nano 2018, 12, 4545−4555. (264) Liu, H.; Du, Y.; Deng, Y.; Ye, P. D. Semiconducting Black Phosphorus: Synthesis, Transport Properties and Electronic Applications. Chem. Soc. Rev. 2015, 44, 2732−2743. (265) Gusmao, R.; Sofer, Z.; Pumera, M. Black Phosphorus Rediscovered: From Bulk Material to Monolayers. Angew. Chem., Int. Ed. 2017, 56, 8052−8072. (266) Yi, Y.; Yu, X.-F.; Zhou, W.; Wang, J.; Chu, P. K. TwoDimensional Black Phosphorus: Synthesis, Modification, Properties, and Applications. Mater. Sci. Eng., R 2017, 120, 1−33. (267) Yang, B.; Yin, J.; Chen, Y.; Pan, S.; Yao, H.; Gao, Y.; Shi, J. 2DBlack-Phosphorus-Reinforced 3D-Printed Scaffolds:A Stepwise Countermeasure for Osteosarcoma. Adv. Mater. 2018, 30, 1705611. (268) Sun, Z.; Xie, H.; Tang, S.; Yu, X. F.; Guo, Z.; Shao, J.; Zhang, H.; Huang, H.; Wang, H.; Chu, P. K. Ultrasmall Black Phosphorus Quantum Dots: Synthesis and Use as Photothermal Agents. Angew. Chem., Int. Ed. 2015, 54, 11526−11530. (269) Yang, B.; Lin, H.; Dai, C.; Chen, Y.; Shi, J. Stepwise Extraction” Strategy-Based Injectable Bioresponsive Composite Implant for Cancer Theranostics. Biomaterials 2018, 166, 38−51. (270) Guo, T.; Wu, Y.; Lin, Y.; Xu, X.; Lian, H.; Huang, G.; Liu, J. Z.; Wu, X.; Yang, H. H. Black Phosphorus Quantum Dots with Renal Clearance Property for Efficient Photodynamic Therapy. Small 2018, 14, 1702815. (271) Tao, W.; Zhu, X.; Yu, X.; Zeng, X.; Xiao, Q.; Zhang, X.; Ji, X.; Wang, X.; Shi, J.; Zhang, H.; et al. Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics. Adv. Mater. 2017, 29, 1603276. (272) Fojtu, M.; Chia, X. Y.; Sofer, Z.; Masarik, M.; Pumera, M. Black Phosphorus Nanoparticles Potentiate the Anticancer Effect of Oxaliplatin in Ovarian Cancer Cell Line. Adv. Funct. Mater. 2017, 27, 1701955. CL


Chemical Reviews

Review

(273) Sun, C.; Wen, L.; Zeng, J.; Wang, Y.; Sun, Q.; Deng, L.; Zhao, C.; Li, Z. One-Pot Solventless Preparation of PEGylated Black Phosphorus Nanoparticles for Photoacoustic Imaging and Photothermal Therapy of Cancer. Biomaterials 2016, 91, 81−89. (274) Sun, Z.; Zhao, Y.; Li, Z.; Cui, H.; Zhou, Y.; Li, W.; Tao, W.; Zhang, H.; Wang, H.; Chu, P. K.; et al. TiL4 -Coordinated Black Phosphorus Quantum Dots as an Efficient Contrast Agent for in Vivo Photoacoustic Imaging of Cancer. Small 2017, 13, 1602896. (275) Pan, X.; Bai, L.; Wang, H.; Wu, Q.; Wang, H.; Liu, S.; Xu, B.; Shi, X.; Liu, H. Metal-Organic-Framework-Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy. Adv. Mater. 2018, 30, 1800180. (276) Yu, L.; Hu, P.; Chen, Y. Gas-Generating Nanoplatforms: Material Chemistry, Multifunctionality, and Gas Therapy. Adv. Mater. 2018, 30, 1801964. (277) Liu, T.; Zhang, N.; Wang, Z.; Wu, M.; Chen, Y.; Ma, M.; Chen, H.; Shi, J. Endogenous Catalytic Generation of O2 Bubbles for in Situ Ultrasound-Guided High Intensity Focused Ultrasound Ablation. ACS Nano 2017, 11, 9093−9102. (278) Jagsi, R. Progress and Controversies: Radiation Therapy for Invasive Breast Cancer. Ca-Cancer J. Clin. 2014, 64, 135−152. (279) Timmerman, R. D.; Bizekis, C. S.; Pass, H. I.; Fong, Y.; Dupuy, D. E.; Dawson, L. A.; Lu, D. Local Surgical, Ablative, and Radiation Treatment of Metastases. Ca-Cancer J. Clin. 2009, 59, 145−170. (280) Bucci, M. K.; Bevan, A.; Roach, M., 3rd Advances in Radiation Therapy: Conventional to 3D, to IMRT, to 4D, and beyond. CaCancer J. Clin. 2005, 55, 117−134. (281) Sadeghi, M.; Enferadi, M.; Shirazi, A. External and Internal Radiation Therapy: Past and Future Directions. J. Cancer Res. Ther. 2010, 6, 239−248. (282) Horwitz, E. M.; Hanks, G. E. External Beam Radiation Therapy for Prostate Cancer. Ca-Cancer J. Clin. 2000, 50, 349−375. (283) D’Amico, A. V. Biochemical Outcome Following External Beam Radiation Therapy with or without Androgen Suppression Therapy for Clinically Localized Prostate Cancer. JAMA 2000, 284, 1280. (284) al-Abany, M.; Steineck, G.; Agren Cronqvist, A. K.; Helgason, A. R. Improving the Preservation of Erectile Function after External Beam Radiation Therapy for Prostate Cancer. Radiother. Oncol. 2000, 57, 201−206. (285) Liang, C.; Xu, L.; Song, G.; Liu, Z. Emerging Nanomedicine Approaches Fighting Tumor Metastasis: Animal Models, MetastasisTargeted Drug Delivery, Phototherapy, and Immunotherapy. Chem. Soc. Rev. 2016, 45, 6250−6269. (286) Guo, Z.; Zhu, S.; Yong, Y.; Zhang, X.; Dong, X. H.; Du, J. F.; Xie, J. N.; Wang, Q.; Gu, Z. J.; Zhao, Y. L. Synthesis of BSA-Coated BiOI@Bi2S3 Semiconductor Heterojunction Nanoparticles and Their Applications for Radio/Photodynamic/Photothermal Synergistic Therapy of Tumor. Adv. Mater. 2017, 29, 1704136. (287) Luksiene, Z.; Juzenas, P.; Moan, J. Radiosensitization of Tumours by Porphyrins. Cancer Lett. 2006, 235, 40−47. (288) Zhang, P.; Qiao, Y.; Wang, C.; Ma, L.; Su, M. Enhanced Radiation Therapy with Internalized Polyelectrolyte Modified Nanoparticles. Nanoscale 2014, 6, 10095−10099. (289) Cheng, K.; Sano, M.; Jenkins, C. H.; Zhang, G.; Vernekohl, D.; Zhao, W.; Wei, C.; Zhang, Y.; Zhang, Z.; Liu, Y.; et al. Synergistically Enhancing the Therapeutic Effect of Radiation Therapy with Radiation Activatable and Reactive Oxygen Species-Releasing Nanostructures. ACS Nano 2018, 12, 4946−4958. (290) Ma, M.; Huang, Y.; Chen, H.; Jia, X.; Wang, S.; Wang, Z.; Shi, J. Bi2S3-Embedded Mesoporous Silica Nanoparticles for Efficient Drug Delivery and Interstitial Radiotherapy Sensitization. Biomaterials 2015, 37, 447−455. (291) Song, Z. H.; Chang, Y. Z.; Xie, H. H.; Yu, X. F.; Chu, P. K.; Chen, T. F. Decorated Ultrathin Bismuth Selenide Nanosheets as Targeted Theranostic Agents for in Vivo Imaging Guided Cancer Radiation Therapy. NPG Asia Mater. 2017, 9, e439. (292) Wang, S.; Li, X.; Chen, Y.; Cai, X.; Yao, H.; Gao, W.; Zheng, Y.; An, X.; Shi, J.; Chen, H. A Facile One-Pot Synthesis of a Two-

Dimensional MoS2/Bi2S3 Composite Theranostic Nanosystem for Multi-Modality Tumor Imaging and Therapy. Adv. Mater. 2015, 27, 2775−2782. (293) Du, J.; Gu, Z.; Yan, L.; Yong, Y.; Yi, X.; Zhang, X.; Liu, J.; Wu, R.; Ge, C.; Chen, C.; et al. Poly(Vinylpyrollidone)- and Selenocysteine-Modified Bi2Se3 Nanoparticles Enhance Radiotherapy Efficacy in Tumors and Promote Radioprotection in Normal Tissues. Adv. Mater. 2017, 29, 1701268. (294) Song, G.; Liang, C.; Gong, H.; Li, M.; Zheng, X.; Cheng, L.; Yang, K.; Jiang, X.; Liu, Z. Core-Shell MnSe@Bi2Se3 Fabricated Via a Cation Exchange Method as Novel Nanotheranostics for Multimodal Imaging and Synergistic Thermoradiotherapy. Adv. Mater. 2015, 27, 6110−6117. (295) Song, G. S.; Chao, Y.; Chen, Y. Y.; Liang, C.; Yi, X.; Yang, G. B.; Yang, K.; Cheng, L.; Zhang, Q.; Liu, Z. All-in-One Theranostic Nanoplatform Based on Hollow TaOx for Chelator-Free Labeling Imaging, Drug Delivery, and Synergistically Enhanced Radiotherapy. Adv. Funct. Mater. 2016, 26, 8243−8254. (296) Song, G.; Chen, Y.; Liang, C.; Yi, X.; Liu, J.; Sun, X.; Shen, S.; Yang, K.; Liu, Z. Catalase-Loaded TaOx Nanoshells as BioNanoreactors Combining High-Z Element and Enzyme Delivery for Enhancing Radiotherapy. Adv. Mater. 2016, 28, 7143−7148. (297) Cheng, L.; Yuan, C.; Shen, S.; Yi, X.; Gong, H.; Yang, K.; Liu, Z. Bottom-up Synthesis of Metal-Ion-Doped WS2 Nanoflakes for Cancer Theranostics. ACS Nano 2015, 9, 11090−11101. (298) Yong, Y.; Zhang, C.; Gu, Z.; Du, J.; Guo, Z.; Dong, X.; Xie, J.; Zhang, G.; Liu, X.; Zhao, Y. Polyoxometalate-Based Radiosensitization Platform for Treating Hypoxic Tumors by Attenuating Radioresistance and Enhancing Radiation Response. ACS Nano 2017, 11, 7164−7176. (299) Lu, K.; He, C.; Guo, N.; Chan, C.; Ni, K.; Lan, G.; Tang, H.; Pelizzari, C.; Fu, Y.-X.; Spiotto, M. T.; et al. Low-Dose X-Ray Radiotherapy-Radiodynamic Therapy Via Nanoscale Metal-Organic Frameworks Enhances Checkpoint Blockade Immunotherapy. Nat. Biomed. Eng. 2018, 2, 600−610. (300) Liu, J.; Yang, Y.; Zhu, W.; Yi, X.; Dong, Z.; Xu, X.; Chen, M.; Yang, K.; Lu, G.; Jiang, L.; et al. Nanoscale Metal-Organic Frameworks for Combined Photodynamic & Radiation Therapy in Cancer Treatment. Biomaterials 2016, 97, 1−9. (301) Yang, Y.; Chao, Y.; Liu, J. J.; Dong, Z. L.; He, W. W.; Zhang, R.; Yang, K.; Chen, M. W.; Liu, Z. Core-Shell and Co-Doped Nanoscale Metal-Organic Particles (NMOPs) Obtained Via PostSynthesis Cation Exchange for Multimodal Imaging and Synergistic Thermo-Radiotherapy. NPG Asia Mater. 2017, 9, e344. (302) Xiao, Q.; Zheng, X.; Bu, W.; Ge, W.; Zhang, S.; Chen, F.; Xing, H.; Ren, Q.; Fan, W.; Zhao, K.; et al. A Core/Satellite Multifunctional Nanotheranostic for in Vivo Imaging and Tumor Eradication by Radiation/Photothermal Synergistic Therapy. J. Am. Chem. Soc. 2013, 135, 13041−13048. (303) Fan, W.; Shen, B.; Bu, W.; Chen, F.; Zhao, K.; Zhang, S.; Zhou, L.; Peng, W.; Xiao, Q.; Xing, H.; et al. Rattle-Structured Multifunctional Nanotheranostics for Synergetic Chemo-/Radiotherapy and Simultaneous Magnetic/Luminescent Dual-Mode Imaging. J. Am. Chem. Soc. 2013, 135, 6494−6503. (304) Szakacs, G.; Hall, M. D.; Gottesman, M. M.; Boumendjel, A.; Kachadourian, R.; Day, B. J.; Baubichon-Cortay, H.; Di Pietro, A. Targeting the Achilles Heel of Multidrug-Resistant Cancer by Exploiting the Fitness Cost of Resistance. Chem. Rev. 2014, 114, 5753−5774. (305) Fan, W.; Yung, B. C.; Chen, X. Stimuli-Responsive NO Release for on-Demand Gas-Sensitized Synergistic Cancer Therapy. Angew. Chem., Int. Ed. 2018, 57, 8383−8394. (306) Liu, F.; Lou, J.; Hristov, D. X-Ray Responsive Nanoparticles with Triggered Release of Nitrite, a Precursor of Reactive Nitrogen Species, for Enhanced Cancer Radiosensitization. Nanoscale 2017, 9, 14627−14634. (307) Frerart, F.; Sonveaux, P.; Rath, G.; Smoos, A.; Meqor, A.; Charlier, N.; Jordan, B. F.; Saliez, J.; Noel, A.; Dessy, C.; et al. The Acidic Tumor Microenvironment Promotes the Reconversion of CM


Chemical Reviews

Review

Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy. Clin. Cancer Res. 2008, 14, 2768−2774. (308) Fan, W.; Lu, N.; Huang, P.; Liu, Y.; Yang, Z.; Wang, S.; Yu, G.; Liu, Y.; Hu, J.; He, Q.; et al. Glucose-Responsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving-Like/Gas Therapy. Angew. Chem., Int. Ed. 2017, 56, 1229−1233. (309) Fan, W.; Bu, W.; Zhang, Z.; Shen, B.; Zhang, H.; He, Q.; Ni, D.; Cui, Z.; Zhao, K.; Bu, J.; et al. X-Ray Radiation-Controlled NORelease for on-Demand Depth-Independent Hypoxic Radiosensitization. Angew. Chem., Int. Ed. 2015, 54, 14026−14030. (310) Dewhirst, M. W.; Cao, Y.; Moeller, B. Cycling Hypoxia and Free Radicals Regulate Angiogenesis and Radiotherapy Response. Nat. Rev. Cancer 2008, 8, 425−437. (311) Prasad, P.; Gordijo, C. R.; Abbasi, A. Z.; Maeda, A.; Ip, A.; Rauth, A. M.; DaCosta, R. S.; Wu, X. Y. Multifunctional AlbuminMnO2 Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response. ACS Nano 2014, 8, 3202−3212. (312) Yi, X.; Chen, L.; Zhong, X. Y.; Gao, R. L.; Qian, Y. T.; Wu, F.; Song, G. S.; Chai, Z. F.; Liu, Z.; Yang, K. Core-Shell Au@MnO2 Nanoparticles for Enhanced Radiotherapy Via Improving the Tumor Oxygenation. Nano Res. 2016, 9, 3267−3278. (313) Meng, L.; Cheng, Y.; Tong, X.; Gan, S.; Ding, Y.; Zhang, Y.; Wang, C.; Xu, L.; Zhu, Y.; Wu, J.; et al. Tumor Oxygenation and Hypoxia Inducible Factor-1 Functional Inhibition Via a Reactive Oxygen Species Responsive Nanoplatform for Enhancing Radiation Therapy and Abscopal Effects. ACS Nano 2018, 12, 8308−8322. (314) Gao, M.; Liang, C.; Song, X.; Chen, Q.; Jin, Q.; Wang, C.; Liu, Z. Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy. Adv. Mater. 2017, 29, 1701429. (315) Murayama, C.; Kawaguchi, A. T.; Ishikawa, K.; Kamijo, A.; Kato, N.; Ohizumi, Y.; Sadahiro, S.; Haida, M. Liposome-Encapsulated Hemoglobin Ameliorates Tumor Hypoxia and Enhances Radiation Therapy to Suppress Tumor Growth in Mice. Artif. Organs 2012, 36, 170−177. (316) Eisenbrey, J. R.; Shraim, R.; Liu, J. B.; Li, J.; Stanczak, M.; Oeffinger, B.; Leeper, D. B.; Keith, S. W.; Jablonowski, L. J.; Forsberg, F.; et al. Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles. Int. J. Radiat. Oncol., Biol., Phys. 2018, 101, 88−96. (317) Chou, S. S.; Kaehr, B.; Kim, J.; Foley, B. M.; De, M.; Hopkins, P. E.; Huang, J.; Brinker, C. J.; Dravid, V. P. Chemically Exfoliated MoS2 as near-Infrared Photothermal Agents. Angew. Chem., Int. Ed. 2013, 52, 4160−4164. (318) Liu, T.; Wang, C.; Gu, X.; Gong, H.; Cheng, L.; Shi, X.; Feng, L.; Sun, B.; Liu, Z. Drug Delivery with PEGylated MoS2 Nano-Sheets for Combined Photothermal and Chemotherapy of Cancer. Adv. Mater. 2014, 26, 3433−3440. (319) Liu, T.; Wang, C.; Cui, W.; Gong, H.; Liang, C.; Shi, X.; Li, Z.; Sun, B.; Liu, Z. Combined Photothermal and Photodynamic Therapy Delivered by PEGylated MoS2 Nanosheets. Nanoscale 2014, 6, 11219−11225. (320) Liu, T.; Shi, S.; Liang, C.; Shen, S.; Cheng, L.; Wang, C.; Song, X.; Goel, S.; Barnhart, T. E.; Cai, W.; et al. Iron Oxide Decorated MoS2 Nanosheets with Double PEGylation for Chelator-Free Radiolabeling and Multimodal Imaging Guided Photothermal Therapy. ACS Nano 2015, 9, 950−960. (321) Wang, S.; Li, K.; Chen, Y.; Chen, H.; Ma, M.; Feng, J.; Zhao, Q.; Shi, J. Biocompatible PEGylated MoS2 Nanosheets: Controllable Bottom-up Synthesis and Highly Efficient Photothermal Regression of Tumor. Biomaterials 2015, 39, 206−217. (322) Xie, J.; Wang, C.; Zhao, F.; Gu, Z.; Zhao, Y. Application of Multifunctional Nanomaterials in Radioprotection of Healthy Tissues. Adv. Healthcare Mater. 2018, 7, 1800421. (323) Colon, J.; Hsieh, N.; Ferguson, A.; Kupelian, P.; Seal, S.; Jenkins, D. W.; Baker, C. H. Cerium Oxide Nanoparticles Protect Gastrointestinal Epithelium from Radiation-Induced Damage by

Reduction of Reactive Oxygen Species and Upregulation of Superoxide Dismutase 2. Nanomedicine 2010, 6, 698−705. (324) Karakoti, A. S.; Singh, S.; Kumar, A.; Malinska, M.; Kuchibhatla, S. V.; Wozniak, K.; Self, W. T.; Seal, S. PEGylated Nanoceria as Radical Scavenger with Tunable Redox Chemistry. J. Am. Chem. Soc. 2009, 131, 14144−14145. (325) Zhang, X. D.; Zhang, J.; Wang, J.; Yang, J.; Chen, J.; Shen, X.; Deng, J.; Deng, D.; Long, W.; Sun, Y. M.; et al. Highly Catalytic Nanodots with Renal Clearance for Radiation Protection. ACS Nano 2016, 10, 4511−4519. (326) Bai, X. T.; Wang, J. Y.; Mu, X. Y.; Yang, J.; Liu, H. X.; Xu, F. J.; Jing, Y. Q.; Liu, L. F.; Xue, X. H.; Dai, H. T.; et al. Ultrasmall WS2 Quantum Dots with Visible Fluorescence for Protection of Cells and Animal Models from Radiation-Induced Damages. ACS Biomater. Sci. Eng. 2017, 3, 460−470. (327) Wang, J. Y.; Mu, X.; Li, Y.; Xu, F.; Long, W.; Yang, J.; Bian, P.; Chen, J.; Ouyang, L.; Liu, H.; et al. Hollow PtPdRh Nanocubes with Enhanced Catalytic Activities for in Vivo Clearance of RadiationInduced ROS Via Surface-Mediated Bond Breaking. Small 2018, 14, 1703736. (328) Rageh, M. M.; El-Gebaly, R. H.; Abou-Shady, H.; Amin, D. G. Melanin Nanoparticles (MNPs) Provide Protection against WholeBody -Irradiation in Mice Via Restoration of Hematopoietic Tissues. Mol. Cell. Biochem. 2015, 399, 59−69. (329) Sayle, T. X.; Sayle, D. C. Visualizing the Enhanced Chemical Reactivity of Mesoporous Ceria; Simulating Templated Crystallization in Silica Scaffolds at the Atomic Level. J. Am. Chem. Soc. 2014, 136, 4056−4065. (330) Asati, A.; Santra, S.; Kaittanis, C.; Nath, S.; Perez, J. M. Oxidase-Like Activity of Polymer-Coated Cerium Oxide Nanoparticles. Angew. Chem., Int. Ed. 2009, 48, 2308−2312. (331) Lin, Y.; Xu, C.; Ren, J.; Qu, X. Using Thermally Regenerable Cerium Oxide Nanoparticles in Biocomputing to Perform Label-Free, Resettable, and Colorimetric Logic Operations. Angew. Chem., Int. Ed. 2012, 51, 12579−12583. (332) Singh, V.; Singh, S.; Das, S.; Kumar, A.; Self, W. T.; Seal, S. A Facile Synthesis of PLGA Encapsulated Cerium Oxide Nanoparticles: Release Kinetics and Biological Activity. Nanoscale 2012, 4, 2597− 2605. (333) Shao, M.; Chang, Q.; Dodelet, J. P.; Chenitz, R. Recent Advances in Electrocatalysts for Oxygen Reduction Reaction. Chem. Rev. 2016, 116, 3594−3657. (334) Xu, Y.; Wang, X.; Zhang, W. L.; Lv, F.; Guo, S. Recent Progress in Two-Dimensional Inorganic Quantum Dots. Chem. Soc. Rev. 2018, 47, 586−625. (335) Kinnear, C.; Moore, T. L.; Rodriguez-Lorenzo, L.; RothenRutishauser, B.; Petri-Fink, A. Form Follows Function: Nanoparticle Shape and Its Implications for Nanomedicine. Chem. Rev. 2017, 117, 11476−11521. (336) Chen, Y.; Chen, H. R.; Shi, J. L. Construction of Homogenous/Heterogeneous Hollow Mesoporous Silica Nanostructures by Silica-Etching Chemistry: Principles, Synthesis, and Applications. Acc. Chem. Res. 2014, 47, 125−137. (337) Gao, S.; Lin, Y.; Jiao, X.; Sun, Y.; Luo, Q.; Zhang, W.; Li, D.; Yang, J.; Xie, Y. Partially Oxidized Atomic Cobalt Layers for Carbon Dioxide Electroreduction to Liquid Fuel. Nature 2016, 529, 68−71. (338) Wan, G.; Yang, C.; Zhao, W.; Li, Q.; Wang, N.; Li, T.; Zhou, H.; Chen, H.; Shi, J. Anion-Regulated Selective Generation of Cobalt Sites in Carbon: Toward Superior Bifunctional Electrocatalysis. Adv. Mater. 2017, 29, 1703436. (339) Masa, J.; Xia, W.; Muhler, M.; Schuhmann, W. On the Role of Metals in Nitrogen-Doped Carbon Electrocatalysts for Oxygen Reduction. Angew. Chem., Int. Ed. 2015, 54, 10102−10120. (340) Jin, H.; Guo, C.; Liu, X.; Liu, J.; Vasileff, A.; Jiao, Y.; Zheng, Y.; Qiao, S. Z. Emerging Two-Dimensional Nanomaterials for Electrocatalysis. Chem. Rev. 2018, 118, 6337−6408. (341) Zeng, L. M.; Cui, X. Z.; Zhang, J. M.; Huang, W. M.; Chen, L. S.; Wei, C. Y.; Shi, J. L. A Facile Strategy to Construct CoOx in Situ CN


Chemical Reviews

Review

Embedded Nanoflowers as an Efficient Electrocatalyst for Oxygen Evolution Reaction. Electrochim. Acta 2018, 275, 218−224. (342) Dadachova, E.; Casadevall, A. Ionizing Radiation: How Fungi Cope, Adapt, and Exploit with the Help of Melanin. Curr. Opin. Microbiol. 2008, 11, 525−531. (343) Schweitzer, A. D.; Howell, R. C.; Jiang, Z.; Bryan, R. A.; Gerfen, G.; Chen, C. C.; Mah, D.; Cahill, S.; Casadevall, A.; Dadachova, E. Physico-Chemical Evaluation of Rationally Designed Melanins as Novel Nature-Inspired Radioprotectors. PLoS One 2009, 4, e7229. (344) Wang, L.; Huo, M.; Chen, Y.; Shi, J. Tumor Microenvironment-Enabled Nanotherapy. Adv. Healthcare Mater. 2018, 7, 1701156. (345) Webb, B. A.; Chimenti, M.; Jacobson, M. P.; Barber, D. L. Dysregulated Ph: A Perfect Storm for Cancer Progression. Nat. Rev. Cancer 2011, 11, 671−677. (346) Estrella, V.; Chen, T.; Lloyd, M.; Wojtkowiak, J.; Cornnell, H. H.; Ibrahim-Hashim, A.; Bailey, K.; Balagurunathan, Y.; Rothberg, J. M.; Sloane, B. F.; et al. Acidity Generated by the Tumor Microenvironment Drives Local Invasion. Cancer Res. 2013, 73, 1524−1535. (347) Schafer, F. Q.; Buettner, G. R. Redox Environment of the Cell as Viewed through the Redox State of the Glutathione Disulfide/ Glutathione Couple. Free Radical Biol. Med. 2001, 30, 1191−1212. (348) Meng, F. H.; Cheng, R.; Deng, C.; Zhong, Z. Y. Intracellular Drug Release Nanosystems. Mater. Today 2012, 15, 436−442. (349) Lin, L. S.; Song, J.; Song, L.; Ke, K.; Liu, Y.; Zhou, Z.; Shen, Z.; Li, J.; Yang, Z.; Tang, W.; et al. Simultaneous Fenton-Like Ion Delivery and Glutathione Depletion by MnO2-Based Nanoagent to Enhance Chemodynamic Therapy. Angew. Chem., Int. Ed. 2018, 57, 4902−4906. (350) Lopez-Lazaro, M. Dual Role of Hydrogen Peroxide in Cancer: Possible Relevance to Cancer Chemoprevention and Therapy. Cancer Lett. 2007, 252, 1−8. (351) Szatrowski, T. P.; Nathan, C. F. Production of Large Amounts of Hydrogen Peroxide by Human Tumor Cells. Cancer Res. 1991, 51, 794−798. (352) Wlassoff, W. A.; Albright, C. D.; Sivashinski, M. S.; Ivanova, A.; Appelbaum, J. G.; Salganik, R. I. Hydrogen Peroxide Overproduced in Breast Cancer Cells Can Serve as an Anticancer Prodrug Generating Apoptosis-Stimulating Hydroxyl Radicals under the Effect of Tamoxifen-Ferrocene Conjugate. J. Pharm. Pharmacol. 2007, 59, 1549−1553. (353) Zhang, C.; Bu, W.; Ni, D.; Zhang, S.; Li, Q.; Yao, Z.; Zhang, J.; Yao, H.; Wang, Z.; Shi, J. Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction. Angew. Chem., Int. Ed. 2016, 55, 2101−2106. (354) Jung, Y. S.; Lim, W. T.; Park, J. Y.; Kim, Y. H. Effect of PH on Fenton and Fenton-Like Oxidation. Environ. Technol. 2009, 30, 183− 190. (355) Imlay, J. A.; Chin, S. M.; Linn, S. Toxic DNA Damage by Hydrogen-Peroxide through the Fenton Reaction In Vivo and In Vitro. Science 1988, 240, 640−642. (356) Xing, M.; Xu, W.; Dong, C.; Bai, Y.; Zeng, J.; Zhou, Y.; Zhang, J.; Yin, Y. Metal Sulfides as Excellent Co-Catalysts for H2O2 Decomposition in Advanced Oxidation Processes. Chem. 2018, 4, 1359−1372. (357) Dixon, S. J.; Stockwell, B. R. The Role of Iron and Reactive Oxygen Species in Cell Death. Nat. Chem. Biol. 2014, 10, 9−17. (358) Shevtsov, M. A.; Parr, M. A.; Ryzhov, V. A.; Zemtsova, E. G.; Arbenin, A. Y.; Ponomareva, A. N.; Smirnov, V. M.; Multhoff, G. ZeroValent Fe Confined Mesoporous Silica Nanocarriers (Fe(0) @ MCM41) for Targeting Experimental Orthotopic Glioma in Rats. Sci. Rep. 2016, 6, 29247. (359) Xu, C.; Yuan, Z.; Kohler, N.; Kim, J.; Chung, M. A.; Sun, S. FePt Nanoparticles as an Fe Reservoir for Controlled Fe Release and Tumor Inhibition. J. Am. Chem. Soc. 2009, 131, 15346−15351. (360) Shi, Y. J.; Lin, M.; Jiang, X. M.; Liang, S. Recent Advances in FePt Nanoparticles for Biomedicine. J. Nanomater. 2015, 2015, 467873.

(361) Shi, J. Amorphous Iron Nanoparticles: Special Structural and Physicochemical Features Enable Chemical Dynamic Therapy for Tumors. Nanomedicine 2016, 11, 1189−1191. (362) Sun, S.; Murray, C. B.; Weller, D.; Folks, L.; Moser, A. Monodisperse FePt Nanoparticles and Ferromagnetic FePt Nanocrystal Superlattices. Science 2000, 287, 1989−1992. (363) Dong, Y. L.; Zhang, H. G.; Rahman, Z. U.; Su, L.; Chen, X. J.; Hu, J.; Chen, X. G. Graphene Oxide-Fe3O4 Magnetic Nanocomposites with Peroxidase-Like Activity for Colorimetric Detection of Glucose. Nanoscale 2012, 4, 3969−3976. (364) Zhao, K.; Gu, W.; Zheng, S.; Zhang, C.; Xian, Y. SDS-MoS2 Nanoparticles as Highly-Efficient Peroxidase Mimetics for Colorimetric Detection of H2O2 and Glucose. Talanta 2015, 141, 47−52. (365) Chen, H. Y.; Li, Y.; Zhang, F. B.; Zhang, G. L.; Fan, X. B. Graphene Supported Au-Pd Bimetallic Nanoparticles with Core-Shell Structures and Superior Peroxidase-Like Activities. J. Mater. Chem. 2011, 21, 17658−17661. (366) Liu, M.; Zhao, H.; Chen, S.; Yu, H.; Quan, X. StimuliResponsive Peroxidase Mimicking at a Smart Graphene Interface. Chem. Commun. 2012, 48, 7055−7057. (367) Wang, Q.; Lei, J.; Deng, S.; Zhang, L.; Ju, H. GrapheneSupported Ferric Porphyrin as a Peroxidase Mimic for Electrochemical DNA Biosensing. Chem. Commun. 2013, 49, 916−918. (368) Guo, Y.; Deng, L.; Li, J.; Guo, S.; Wang, E.; Dong, S. HeminGraphene Hybrid Nanosheets with Intrinsic Peroxidase-Like Activity for Label-Free Colorimetric Detection of Single-Nucleotide Polymorphism. ACS Nano 2011, 5, 1282−1290. (369) Wei, H.; Wang, E. Nanomaterials with Enzyme-Like Characteristics (Nanozymes): Next-Generation Artificial Enzymes. Chem. Soc. Rev. 2013, 42, 6060−6093. (370) Yang, B. W.; Chen, Y.; Shi, J. L. Nanozymes in Catalytic Cancer Theranostics. Prog. Biochem. Biophys. 2018, 45, 237−255. (371) Johansson, J. Synthesis: Regime Change for Nanowire Growth. Nat. Nanotechnol. 2007, 2, 534−535. (372) Liu, S.; Lu, F.; Xing, R.; Zhu, J. J. Structural Effects of Fe3O4 Nanocrystals on Peroxidase-Like Activity. Chem. - Eur. J. 2011, 17, 620−625. (373) Kim, M. I.; Shim, J.; Li, T.; Lee, J.; Park, H. G. Fabrication of Nanoporous Nanocomposites Entrapping Fe3O4 Magnetic Nanoparticles and Oxidases for Colorimetric Biosensing. Chem. - Eur. J. 2011, 17, 10700−10707. (374) Zhuang, J.; Fan, K.; Gao, L.; Lu, D.; Feng, J.; Yang, D.; Gu, N.; Zhang, Y.; Liang, M.; Yan, X. Ex Vivo Detection of Iron Oxide Magnetic Nanoparticles in Mice Using Their Intrinsic PeroxidaseMimicking Activity. Mol. Pharmaceutics 2012, 9, 1983−1989. (375) Huang, D. M.; Hsiao, J. K.; Chen, Y. C.; Chien, L. Y.; Yao, M.; Chen, Y. K.; Ko, B. S.; Hsu, S. C.; Tai, L. A.; et al. The Promotion of Human Mesenchymal Stem Cell Proliferation by Superparamagnetic Iron Oxide Nanoparticles. Biomaterials 2009, 30, 3645−3651. (376) Chang, Q.; Deng, K. J.; Zhu, L. H.; Jiang, G. D.; Yu, C.; Tang, H. Q. Determination of Hydrogen Peroxide with the Aid of Peroxidase-Like Fe3O4 Magnetic Nanoparticles as the Catalyst. Microchim. Acta 2009, 165, 299−305. (377) Liu, S.; Tian, J.; Wang, L.; Luo, Y.; Chang, G.; Sun, X. IronSubstituted SBA-15 Microparticles: A Peroxidase-Like Catalyst for H2O2 Detection. Analyst 2011, 136, 4894−4897. (378) Chen, Z.; Yin, J. J.; Zhou, Y. T.; Zhang, Y.; Song, L.; Song, M.; Hu, S.; Gu, N. Dual Enzyme-Like Activities of Iron Oxide Nanoparticles and Their Implication for Diminishing Cytotoxicity. ACS Nano 2012, 6, 4001−4012. (379) Zhang, D.; Zhao, Y. X.; Gao, Y. J.; Gao, F. P.; Fan, Y. S.; Li, X. J.; Duan, Z. Y.; Wang, H. Anti-Bacterial and in Vivo Tumor Treatment by Reactive Oxygen Species Generated by Magnetic Nanoparticles. J. Mater. Chem. B 2013, 1, 5100−5107. (380) Fu, J.; Shao, Y.; Wang, L.; Zhu, Y. Lysosome-Controlled Efficient ROS Overproduction against Cancer Cells with a High PHResponsive Catalytic Nanosystem. Nanoscale 2015, 7, 7275−7283. (381) Wang, L.; Huo, M.; Chen, Y.; Shi, J. Iron-Engineered Mesoporous Silica Nanocatalyst with Biodegradable and Catalytic CO


Chemical Reviews

Review

Framework for Tumor-Specific Therapy. Biomaterials 2018, 163, 1− 13. (382) Wang, L.; Huo, M.; Chen, Y.; Shi, J. Coordination-Accelerated “Iron Extraction” Enables Fast Biodegradation of Mesoporous SilicaBased Hollow Nanoparticles. Adv. Healthcare Mater. 2017, 6, 1700720. (383) Bokare, A. D.; Choi, W. Review of Iron-Free Fenton-Like Systems for Activating H2O2 in Advanced Oxidation Processes. J. Hazard. Mater. 2014, 275, 121−135. (384) Gawande, M. B.; Goswami, A.; Felpin, F. X.; Asefa, T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S. Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis. Chem. Rev. 2016, 116, 3722−3811. (385) Masarwa, M.; Cohen, H.; Meyerstein, D.; Hickman, D. L.; Bakac, A.; Espenson, J. H. Reactions of Low-Valent Transition-Metal Complexes with Hydrogen Peroxide. Are They “Fenton-Like” or Not? 1. The Case of Cu+aq and Cr2+aq. J. Am. Chem. Soc. 1988, 110, 4293− 4297. (386) Lee, H.; Lee, H. J.; Sedlak, D. L.; Lee, C. PH-Dependent Reactivity of Oxidants Formed by Iron and Copper-Catalyzed Decomposition of Hydrogen Peroxide. Chemosphere 2013, 92, 652− 658. (387) Pham, A. N.; Xing, G. W.; Miller, C. J.; Waite, T. D. FentonLike Copper Redox Chemistry Revisited: Hydrogen Peroxide and Superoxide Mediation of Copper-Catalyzed Oxidant Production. J. Catal. 2013, 301, 54−64. (388) Wang, Z.; von dem Bussche, A.; Kabadi, P. K.; Kane, A. B.; Hurt, R. H. Biological and Environmental Transformations of CopperBased Nanomaterials. ACS Nano 2013, 7, 8715−8727. (389) Lee, H.; Seong, J.; Lee, K. M.; Kim, H. H.; Choi, J.; Kim, J. H.; Lee, C. Chloride-Enhanced Oxidation of Organic Contaminants by Cu(II)-Catalyzed Fenton-Like Reaction at Neutral PH. J. Hazard. Mater. 2018, 344, 1174−1180. (390) Nie, G. D.; Li, Z. C.; Lu, X. F.; Lei, J. Y.; Zhang, C. C.; Wang, C. Fabrication of Polyacrylonitrile/CuS Composite Nanofibers and Their Recycled Application in Catalysis for Dye Degradation. Appl. Surf. Sci. 2013, 284, 595−600. (391) Liu, Y.; Zhen, W.; Jin, L.; Zhang, S.; Sun, G.; Zhang, T.; Xu, X.; Song, S.; Wang, Y.; Liu, J.; et al. All-in-One Theranostic Nanoagent with Enhanced Reactive Oxygen Species Generation and Modulating Tumor Microenvironment Ability for Effective Tumor Eradication. ACS Nano 2018, 12, 4886−4893. (392) Gui, L.; Zhou, J. H.; Zhou, L.; Wei, S. H. A Smart CopperPhthalocyanine Framework Nanoparticle for Enhancing Photodynamic Therapy in Hypoxic Conditions by Weakening Cells through ATP Depletion. J. Mater. Chem. B 2018, 6, 2078−2088. (393) Skrott, Z.; Mistrik, M.; Andersen, K. K.; Friis, S.; Majera, D.; Gursky, J.; Ozdian, T.; Bartkova, J.; Turi, Z.; Moudry, P.; et al. Alcohol-Abuse Drug Disulfiram Targets Cancer Via P97 Segregase Adaptor Npl4. Nature 2017, 552, 194−199. (394) Fan, K.; Xi, J.; Fan, L.; Wang, P.; Zhu, C.; Tang, Y.; Xu, X.; Liang, M.; Jiang, B.; Yan, X.; et al. In Vivo Guiding Nitrogen-Doped Carbon Nanozyme for Tumor Catalytic Therapy. Nat. Commun. 2018, 9, 1440. (395) Hu, P.; Wu, T.; Fan, W.; Chen, L.; Liu, Y.; Ni, D.; Bu, W.; Shi, J. Near Infrared-Assisted Fenton Reaction for Tumor-Specific and Mitochondrial DNA-Targeted Photochemotherapy. Biomaterials 2017, 141, 86−95. (396) Li, W. P.; Su, C. H.; Chang, Y. C.; Lin, Y. J.; Yeh, C. S. Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome. ACS Nano 2016, 10, 2017−2027. (397) Ma, P.; Xiao, H.; Yu, C.; Liu, J.; Cheng, Z.; Song, H.; Zhang, X.; Li, C.; Wang, J.; Gu, Z.; et al. Enhanced Cisplatin Chemotherapy by Iron Oxide Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species. Nano Lett. 2017, 17, 928−937. (398) Dai, Y.; Yang, Z.; Cheng, S.; Wang, Z.; Zhang, R.; Zhu, G.; Wang, Z.; Yung, B. C.; Tian, R.; Jacobson, O.; et al. Toxic Reactive Oxygen Species Enhanced Synergistic Combination Therapy by Self-

Assembled Metal-Phenolic Network Nanoparticles. Adv. Mater. 2018, 30, 1704877. (399) Dai, Y.; Cheng, S.; Wang, Z.; Zhang, R.; Yang, Z.; Wang, J.; Yung, B. C.; Wang, Z.; Jacobson, O.; Xu, C.; et al. Hypochlorous Acid Promoted Platinum Drug Chemotherapy by MyeloperoxidaseEncapsulated Therapeutic Metal Phenolic Nanoparticles. ACS Nano 2018, 12, 455−463. (400) Fu, L. H.; Qi, C.; Lin, J.; Huang, P. Catalytic Chemistry of Glucose Oxidase in Cancer Diagnosis and Treatment. Chem. Soc. Rev. 2018, 47, 6454−6472. (401) Fu, J. K.; Zhu, Y. C.; Zhao, Y. Controlled Free Radical Generation against Tumor Cells by PH-Responsive Mesoporous Silica Nanocomposite. J. Mater. Chem. B 2014, 2, 3538−3548. (402) Fu, J. K.; Shao, Y. R.; Shi, C.; Bu, W. B.; Zhu, Y. C. Selective Intracellular Free Radical Generation against Cancer Cells by Bioactivation of Low-Dose Artesunate with a Functionalized Mesoporous Silica Nanosystem. J. Mater. Chem. B 2014, 2, 6984− 6994. (403) He, C.; Lu, K.; Liu, D.; Lin, W. Nanoscale Metal-Organic Frameworks for the Co-Delivery of Cisplatin and Pooled SiRNAs to Enhance Therapeutic Efficacy in Drug-Resistant Ovarian Cancer Cells. J. Am. Chem. Soc. 2014, 136, 5181−5184. (404) Wang, S.; McGuirk, C. M.; d’Aquino, A.; Mason, J. A.; Mirkin, C. A. Metal-Organic Framework Nanoparticles. Adv. Mater. 2018, 30, 1800202. (405) Lu, K.; Aung, T.; Guo, N.; Weichselbaum, R.; Lin, W. Nanoscale Metal-Organic Frameworks for Therapeutic, Imaging, and Sensing Applications. Adv. Mater. 2018, 30, 1707634. (406) Abanades Lazaro, I.; Haddad, S.; Sacca, S.; Orellana-Tavra, C.; Fairen-Jimenez, D.; Forgan, R. S. Selective Surface PEGylation of UiO66 Nanoparticles for Enhanced Stability, Cell Uptake, and PHResponsive Drug Delivery. Chem. 2017, 2, 561−578. (407) Lian, X.; Huang, Y.; Zhu, Y.; Fang, Y.; Zhao, R.; Joseph, E.; Li, J.; Pellois, J. P.; Zhou, H. C. Enzyme-MOF Nanoreactor Activates Nontoxic Paracetamol for Cancer Therapy. Angew. Chem., Int. Ed. 2018, 57, 5725−5730. (408) Wang, D. D.; Zhou, J. J.; Chen, R. H.; Ship, R. H.; Wang, C. L.; Lu, J.; Zhao, G. Z.; Xia, G. L.; Zhou, S.; Liu, Z. B.; et al. Core-Shell Metal-Organic Frameworks as Fe2+ Suppliers for Fe2+-Mediated Cancer Therapy under Multimodality Imaging. Chem. Mater. 2017, 29, 3477−3489. (409) Zhou, Z.; Song, J.; Tian, R.; Yang, Z.; Yu, G.; Lin, L.; Zhang, G.; Fan, W.; Zhang, F.; Niu, G.; et al. Activatable Singlet Oxygen Generation from Lipid Hydroperoxide Nanoparticles for Cancer Therapy. Angew. Chem., Int. Ed. 2017, 56, 6492−6496. (410) Thakor, A. S.; Gambhir, S. S. Nanooncology: The Future of Cancer Diagnosis and Therapy. Ca-Cancer J. Clin. 2013, 63, 395−418. (411) He, Q.; Shi, J. MSN Anti-Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition. Adv. Mater. 2014, 26, 391−411. (412) Curigliano, G.; Cardinale, D.; Dent, S.; Criscitiello, C.; Aseyev, O.; Lenihan, D.; Cipolla, C. M. Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection, and Management. Ca-Cancer J. Clin. 2016, 66, 309−325. (413) Park, S. B.; Goldstein, D.; Krishnan, A. V.; Lin, C. S.; Friedlander, M. L.; Cassidy, J.; Koltzenburg, M.; Kiernan, M. C. Chemotherapy-Induced Peripheral Neurotoxicity: A Critical Analysis. Ca-Cancer J. Clin. 2013, 63, 419−437. (414) Zhu, Y.; Shi, J.; Shen, W.; Dong, X.; Feng, J.; Ruan, M.; Li, Y. Stimuli-Responsive Controlled Drug Release from a Hollow Mesoporous Silica Sphere/Polyelectrolyte Multilayer Core-Shell Structure. Angew. Chem., Int. Ed. 2005, 44, 5083−5087. (415) Wu, M.; Meng, Q.; Chen, Y.; Zhang, L.; Li, M.; Cai, X.; Li, Y.; Yu, P.; Zhang, L.; Shi, J. Large Pore-Sized Hollow Mesoporous Organosilica for Redox-Responsive Gene Delivery and Synergistic Cancer Chemotherapy. Adv. Mater. 2016, 28, 1963−1969. (416) Bernardos, A.; Aznar, E.; Marcos, M. D.; Martinez-Manez, R.; Sancenon, F.; Soto, J.; Barat, J. M.; Amoros, P. Enzyme-Responsive CP


Chemical Reviews

Review

Controlled Release Using Mesoporous Silica Supports Capped with Lactose. Angew. Chem., Int. Ed. 2009, 48, 5884−5887. (417) Feng, L. L.; Gai, S. L.; Dai, Y. L.; He, F.; Sun, C. Q.; Yang, P. P.; Lv, R. C.; Niu, N.; An, G. H.; Lin, J. Controllable Generation of Free Radicals from Multifunctional Heat-Responsive Nanoplatform for Targeted Cancer Therapy. Chem. Mater. 2018, 30, 526−539. (418) Liu, J.; Bu, W.; Pan, L.; Shi, J. NIR-Triggered Anticancer Drug Delivery by Upconverting Nanoparticles with Integrated AzobenzeneModified Mesoporous Silica. Angew. Chem., Int. Ed. 2013, 52, 4375− 4379. (419) Wu, M.; Chen, W.; Chen, Y.; Zhang, H.; Liu, C.; Deng, Z.; Sheng, Z.; Chen, J.; Liu, X.; Yan, F.; et al. Focused UltrasoundAugmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging-Guided Brain Tumor Treatment. Adv. Sci. 2018, 5, 1700474. (420) Zhao, W.; Gu, J.; Zhang, L.; Chen, H.; Shi, J. Fabrication of Uniform Magnetic Nanocomposite Spheres with a Magnetic Core/ Mesoporous Silica Shell Structure. J. Am. Chem. Soc. 2005, 127, 8916− 8917. (421) Kamaly, N.; Yameen, B.; Wu, J.; Farokhzad, O. C. Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release. Chem. Rev. 2016, 116, 2602−2663. (422) Karimi, M.; Ghasemi, A.; Sahandi Zangabad, P.; Rahighi, R.; Moosavi Basri, S. M.; Mirshekari, H.; Amiri, M.; Shafaei Pishabad, Z.; Aslani, A.; Bozorgomid, M.; et al. Smart Micro/Nanoparticles in Stimulus-Responsive Drug/Gene Delivery Systems. Chem. Soc. Rev. 2016, 45, 1457−1501. (423) Wang, Y. F.; Kohane, D. S. External Triggering and Triggered Targeting Strategies for Drug Delivery. Nat. Rev. Mater. 2017, 2, 17020. (424) Tapeinos, C.; Pandit, A. Physical, Chemical, and Biological Structures Based on ROS-Sensitive Moieties That Are Able to Respond to Oxidative Microenvironments. Adv. Mater. 2016, 28, 5553−5585. (425) Ge, Z.; Liu, S. Functional Block Copolymer Assemblies Responsive to Tumor and Intracellular Microenvironments for SiteSpecific Drug Delivery and Enhanced Imaging Performance. Chem. Soc. Rev. 2013, 42, 7289−7325. (426) Colson, Y. L.; Grinstaff, M. W. Biologically Responsive Polymeric Nanoparticles for Drug Delivery. Adv. Mater. 2012, 24, 3878−3886. (427) Li, Y.; Bai, H.; Wang, H.; Shen, Y.; Tang, G.; Ping, Y. Reactive Oxygen Species (ROS)-Responsive Nanomedicine for RNAi-Based Cancer Therapy. Nanoscale 2018, 10, 203−214. (428) Li, Y.; Wang, Y.; Huang, G.; Gao, J. Cooperativity Principles in Self-Assembled Nanomedicine. Chem. Rev. 2018, 118, 5359−5391. (429) Wang, L.; Fan, F.; Cao, W.; Xu, H. Ultrasensitive ROSResponsive Coassemblies of Tellurium-Containing Molecules and Phospholipids. ACS Appl. Mater. Interfaces 2015, 7, 16054−16060. (430) Wu, Y. J.; Zhou, D. F.; Qi, Y. X.; Xie, Z. G.; Chen, X. S.; Jing, X. B.; Huang, Y. B. Novel Multi-Sensitive Pseudo-Poly(Amino Acid) for Effective Intracellular Drug Delivery. RSC Adv. 2015, 5, 31972− 31983. (431) Zhai, S.; Hu, X.; Hu, Y.; Wu, B.; Xing, D. Visible Light-Induced Crosslinking and Physiological Stabilization of Diselenide-Rich Nanoparticles for Redox-Responsive Drug Release and Combination Chemotherapy. Biomaterials 2017, 121, 41−54. (432) Wang, J.; Sun, X.; Mao, W.; Sun, W.; Tang, J.; Sui, M.; Shen, Y.; Gu, Z. Tumor Redox Heterogeneity-Responsive Prodrug Nanocapsules for Cancer Chemotherapy. Adv. Mater. 2013, 25, 3670−3676. (433) Xu, X.; Saw, P. E.; Tao, W.; Li, Y.; Ji, X.; Bhasin, S.; Liu, Y.; Ayyash, D.; Rasmussen, J.; Huo, M.; et al. ROS-Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy. Adv. Mater. 2017, 29, 1700141. (434) Pei, Y.; Li, M.; Hou, Y.; Hu, Y.; Chu, G.; Dai, L.; Li, K.; Xing, Y.; Tao, B.; Yu, Y.; et al. An Autonomous Tumor-Targeted Nanoprodrug for Reactive Oxygen Species-Activatable Dual-Cytochrome C/Doxorubicin Antitumor Therapy. Nanoscale 2018, 10, 11418−11429.

(435) Krol, S.; Macrez, R.; Docagne, F.; Defer, G.; Laurent, S.; Rahman, M.; Hajipour, M. J.; Kehoe, P. G.; Mahmoudi, M. Therapeutic Benefits from Nanoparticles: The Potential Significance of Nanoscience in Diseases with Compromise to the Blood Brain Barrier. Chem. Rev. 2013, 113, 1877−1903. (436) Van Meir, E. G.; Hadjipanayis, C. G.; Norden, A. D.; Shu, H. K.; Wen, P. Y.; Olson, J. J. Exciting New Advances in NeuroOncology: The Avenue to a Cure for Malignant Glioma. Ca-Cancer J. Clin. 2010, 60, 166−193. (437) Qiao, C.; Yang, J.; Shen, Q.; Liu, R.; Li, Y.; Shi, Y.; Chen, J.; Shen, Y.; Xiao, Z.; Weng, J.; et al. Traceable Nanoparticles with Dual Targeting and ROS Response for RNAi-Based Immunochemotherapy of Intracranial Glioblastoma Treatment. Adv. Mater. 2018, 30, 1705054. (438) Gordijo, C. R.; Abbasi, A. Z.; Amini, M. A.; Lip, H. Y.; Maeda, A.; Cai, P.; O’Brien, P. J.; DaCosta, R. S.; Rauth, A. M.; Wu, X. Y. Design of Hybrid MnO2-Polymer-Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment. Adv. Funct. Mater. 2015, 25, 1858−1872. (439) Zhao, Z.; Fan, H.; Zhou, G.; Bai, H.; Liang, H.; Wang, R.; Zhang, X.; Tan, W. Activatable Fluorescence/MRI Bimodal Platform for Tumor Cell Imaging Via MnO2 Nanosheet-Aptamer Nanoprobe. J. Am. Chem. Soc. 2014, 136, 11220−11223. (440) Hao, Y.; Wang, L.; Zhang, B.; Zhao, H.; Niu, M.; Hu, Y.; Zheng, C.; Zhang, H.; Chang, J.; Zhang, Z.; et al. Multifunctional Nanosheets Based on Folic Acid Modified Manganese Oxide for Tumor-Targeting Theranostic Application. Nanotechnology 2016, 27, 025101. (441) Song, M.; Liu, T.; Shi, C.; Zhang, X.; Chen, X. Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-Like Phenotype and Attenuating Tumor Hypoxia. ACS Nano 2016, 10, 633−647. (442) Zhang, S.; Qian, X.; Zhang, L.; Peng, W.; Chen, Y. Composition-Property Relationships in Multifunctional Hollow Mesoporous Carbon Nanosystems for PH-Responsive Magnetic Resonance Imaging and on-Demand Drug Release. Nanoscale 2015, 7, 7632−7643. (443) Meng, H. M.; Lu, L.; Zhao, X. H.; Chen, Z.; Zhao, Z.; Yang, C.; Zhang, X. B.; Tan, W. Multiple Functional Nanoprobe for ContrastEnhanced Bimodal Cellular Imaging and Targeted Therapy. Anal. Chem. 2015, 87, 4448−4454. (444) Zhang, W. T.; Li, S. H.; Liu, X. N.; Yang, C. Y.; Hu, N.; Dou, L. N.; Zhao, B. X.; Zhang, Q. Y.; Suo, Y. R.; Wang, J. L. OxygenGenerating MnO2 Nanodots-Anchored Versatile Nanoplatform for Combined Chemo-Photodynamic Therapy in Hypoxic Cancer. Adv. Funct. Mater. 2018, 28, 1706375. (445) Hao, Y.; Wang, L.; Zhang, B.; Li, D.; Meng, D.; Shi, J.; Zhang, H.; Zhang, Z.; Zhang, Y. Manganese Dioxide Nanosheets-Based Redox/PH-Responsive Drug Delivery System for Cancer Theranostic Application. Int. J. Nanomed. 2016, 11, 1759−1778. (446) Ye, M.; Han, Y.; Tang, J.; Piao, Y.; Liu, X.; Zhou, Z.; Gao, J.; Rao, J.; Shen, Y. A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers. Adv. Mater. 2017, 29, 1702342. (447) Wang, C.; Wang, J.; Zhang, X.; Yu, S.; Wen, D.; Hu, Q.; Ye, Y.; Bomba, H.; Hu, X.; Liu, Z.; et al. In Situ Formed Reactive Oxygen Species-Responsive Scaffold with Gemcitabine and Checkpoint Inhibitor for Combination Therapy. Sci. Transl. Med. 2018, 10, eaan3682. (448) Yu, S.; Wang, C.; Yu, J.; Wang, J.; Lu, Y.; Zhang, Y.; Zhang, X.; Hu, Q.; Sun, W.; He, C.; et al. Injectable Bioresponsive Gel Depot for Enhanced Immune Checkpoint Blockade. Adv. Mater. 2018, 30, 1801527. (449) Konstantinidou, M.; Zarganes-Tzitzikas, T.; Magiera-Mularz, K.; Holak, T. A.; Domling, A. Immune Checkpoint PD-1/PD-L1: Is There Life Beyond Antibodies? Angew. Chem., Int. Ed. 2018, 57, 4840− 4848. CQ


Chemical Reviews

Review

(450) Liu, X. Y.; Chu, P. K.; Ding, C. X. Surface Modification of Titanium, Titanium Alloys, and Related Materials for Biomedical Applications. Mater. Sci. Eng., R 2004, 47, 49−121. (451) Yang, B.; Gu, Z.; Chen, Y. Nanomedicine-Augmented CancerLocalized Treatment by 3D Theranostic Implants. J. Biomed. Nanotechnol. 2017, 13, 871−890. (452) Wang, D. H.; Peng, F.; Li, J. H.; Qiao, Y. Q.; Li, Q. W.; Liu, X. Y. Butyrate-Inserted Ni-Ti Layered Double Hydroxide Film for H2O2Mediated Tumor and Bacteria Killing. Mater. Today 2017, 20, 238− 257. (453) Chen, H.; He, W.; Guo, Z. An H2O2-Responsive Nanocarrier for Dual-Release of Platinum Anticancer Drugs and O2: Controlled Release and Enhanced Cytotoxicity against Cisplatin Resistant Cancer Cells. Chem. Commun. 2014, 50, 9714−9717. (454) Chen, H.; Tian, J.; He, W.; Guo, Z. H2O2-Activatable and O2Evolving Nanoparticles for Highly Efficient and Selective Photodynamic Therapy against Hypoxic Tumor Cells. J. Am. Chem. Soc. 2015, 137, 1539−1547. (455) Kagan, D.; Benchimol, M. J.; Claussen, J. C.; Chuluun-Erdene, E.; Esener, S.; Wang, J. Acoustic Droplet Vaporization and Propulsion of Perfluorocarbon-Loaded Microbullets for Targeted Tissue Penetration and Deformation. Angew. Chem., Int. Ed. 2012, 51, 7519−7522. (456) Balasubramanian, S.; Kagan, D.; Hu, C. M.; Campuzano, S.; Lobo-Castanon, M. J.; Lim, N.; Kang, D. Y.; Zimmerman, M.; Zhang, L.; Wang, J. Micromachine-Enabled Capture and Isolation of Cancer Cells in Complex Media. Angew. Chem., Int. Ed. 2011, 50, 4161−4164. (457) Palagi, S.; Fischer, P. Bioinspired Microrobots. Nat. Rev. Mater. 2018, 3, 113−124. (458) Mirkovic, T.; Zacharia, N. S.; Scholes, G. D.; Ozin, G. A. Nanolocomotion - Catalytic Nanomotors and Nanorotors. Small 2010, 6, 159−167. (459) Li, J.; Rozen, I.; Wang, J. Rocket Science at the Nanoscale. ACS Nano 2016, 10, 5619−5634. (460) Jurado-Sanchez, B.; Pacheco, M.; Rojo, J.; Escarpa, A. Magnetocatalytic Graphene Quantum Dots Janus Micromotors for Bacterial Endotoxin Detection. Angew. Chem., Int. Ed. 2017, 56, 6957− 6961. (461) Kim, K.; Guo, J. H.; Liang, Z. X.; Fan, D. L. Artificial Micro/ Nanomachines for Bioapplications: Biochemical Delivery and Diagnostic Sensing. Adv. Funct. Mater. 2018, 28, 1705867. (462) Ma, X.; Katuri, J.; Zeng, Y.; Zhao, Y.; Sanchez, S. Surface Conductive Graphene-Wrapped Micromotors Exhibiting Enhanced Motion. Small 2015, 11, 5023−5027. (463) Laocharoensuk, R.; Burdick, J.; Wang, J. Carbon-NanotubeInduced Acceleration of Catalytic Nanomotors. ACS Nano 2008, 2, 1069−1075. (464) Wu, Z. G.; Li, J. X.; de Avila, B. E. F.; Li, T. L.; Gao, W. W.; He, Q.; Zhang, L. F.; Wang, J. Water-Powered Cell-Mimicking Janus Micromotor. Adv. Funct. Mater. 2015, 25, 7497−7501. (465) Wang, H.; Pumera, M. Emerging Materials for the Fabrication of Micro/Nanomotors. Nanoscale 2017, 9, 2109−2116. (466) Kagan, D.; Calvo-Marzal, P.; Balasubramanian, S.; Sattayasamitsathit, S.; Manesh, K. M.; Flechsig, G. U.; Wang, J. Chemical Sensing Based on Catalytic Nanomotors: Motion-Based Detection of Trace Silver. J. Am. Chem. Soc. 2009, 131, 12082−12083. (467) Wu, J.; Balasubramanian, S.; Kagan, D.; Manesh, K. M.; Campuzano, S.; Wang, J. Motion-Based DNA Detection Using Catalytic Nanomotors. Nat. Commun. 2010, 1, 36. (468) Singh, V. V.; Kaufmann, K.; de Avila, B. E. F.; Karshalev, E.; Wang, J. Molybdenum Disulfide-Based Tubular Microengines: Toward Biomedical Applications. Adv. Funct. Mater. 2016, 26, 6270−6278. (469) Dong, R.; Zhang, Q.; Gao, W.; Pei, A.; Ren, B. Highly Efficient Light-Driven TiO2-Au Janus Micromotors. ACS Nano 2016, 10, 839− 844. (470) Xuan, M.; Wu, Z.; Shao, J.; Dai, L.; Si, T.; He, Q. Near Infrared Light-Powered Janus Mesoporous Silica Nanoparticle Motors. J. Am. Chem. Soc. 2016, 138, 6492−6497.

(471) Peng, F.; Tu, Y.; Men, Y.; van Hest, J. C.; Wilson, D. A. Supramolecular Adaptive Nanomotors with Magnetotaxis Behavior. Adv. Mater. 2017, 29, 1604996. (472) Zhou, F. Y.; Feng, B.; Wang, T. T.; Wang, D. G.; Cui, Z. R.; Wang, S. L.; Ding, C. Y.; Zhang, Z. W.; Liu, J.; Yu, H. J.; et al. Theranostic Prodrug Vesicles for Reactive Oxygen Species-Triggered Ultrafast Drug Release and Local-Regional Therapy of Metastatic Triple-Negative Breast Cancer. Adv. Funct. Mater. 2017, 27, 1703674. (473) Cao, Z. Y.; Ma, Y. C.; Sun, C. Y.; Lu, Z. D.; Yao, Z. Y.; Wang, J. X.; Li, D. D.; Yuan, Y. Y.; Yang, X. Z. ROS-Sensitive Polymeric Nanocarriers with Red Light-Activated Size Shrinkage for Remotely Controlled Drug Release. Chem. Mater. 2018, 30, 517−525. (474) Ruskowitz, E. R.; DeForest, C. A. Photoresponsive Biomaterials for Targeted Drug Delivery and 4D Cell Culture. Nat. Rev. Mater. 2018, 3, 17087. (475) Li, F.; Li, T.; Cao, W.; Wang, L.; Xu, H. Near-Infrared Light Stimuli-Responsive Synergistic Therapy Nanoplatforms Based on the Coordination of Tellurium-Containing Block Polymer and Cisplatin for Cancer Treatment. Biomaterials 2017, 133, 208−218. (476) Qian, C.; Yu, J.; Chen, Y.; Hu, Q.; Xiao, X.; Sun, W.; Wang, C.; Feng, P.; Shen, Q. D.; Gu, Z. Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy. Adv. Mater. 2016, 28, 3313−3320. (477) Shi, J.; Chen, Z.; Wang, B.; Wang, L.; Lu, T.; Zhang, Z. Reactive Oxygen Species-Manipulated Drug Release from a Smart Envelope-Type Mesoporous Titanium Nanovehicle for Tumor Sonodynamic-Chemotherapy. ACS Appl. Mater. Interfaces 2015, 7, 28554−28565. (478) Cleary, A. S.; Leonard, T. L.; Gestl, S. A.; Gunther, E. J. Tumour Cell Heterogeneity Maintained by Cooperating Subclones in Wnt-Driven Mammary Cancers. Nature 2014, 508, 113−117. (479) Hartshorn, C. M.; Bradbury, M. S.; Lanza, G. M.; Nel, A. E.; Rao, J.; Wang, A. Z.; Wiesner, U. B.; Yang, L.; Grodzinski, P. Nanotechnology Strategies to Advance Outcomes in Clinical Cancer Care. ACS Nano 2018, 12, 24−43. (480) Seluanov, A.; Gladyshev, V. N.; Vijg, J.; Gorbunova, V. Mechanisms of Cancer Resistance in Long-Lived Mammals. Nat. Rev. Cancer 2018, 18, 433−441. (481) Chen, Y.; Chen, H.; Shi, J. Inorganic Nanoparticle-Based Drug Codelivery Nanosystems to Overcome the Multidrug Resistance of Cancer Cells. Mol. Pharmaceutics 2014, 11, 2495−2510. (482) Sun, L.; Wang, D.; Chen, Y.; Wang, L.; Huang, P.; Li, Y.; Liu, Z.; Yao, H.; Shi, J. Core-Shell Hierarchical Mesostructured Silica Nanoparticles for Gene/Chemo-Synergetic Stepwise Therapy of Multidrug-Resistant Cancer. Biomaterials 2017, 133, 219−228. (483) Zeng, L.; Pan, Y.; Tian, Y.; Wang, X.; Ren, W.; Wang, S.; Lu, G.; Wu, A. Doxorubicin-Loaded NaYF4:Yb/Tm-TiO2 Inorganic Photosensitizers for NIR-Triggered Photodynamic Therapy and Enhanced Chemotherapy in Drug-Resistant Breast Cancers. Biomaterials 2015, 57, 93−106. (484) Chen, W.; Ouyang, J.; Liu, H.; Chen, M.; Zeng, K.; Sheng, J.; Liu, Z.; Han, Y.; Wang, L.; Li, J.; et al. Black Phosphorus NanosheetBased Drug Delivery System for Synergistic Photodynamic/Photothermal/Chemotherapy of Cancer. Adv. Mater. 2017, 29, 1603864. (485) Herrera, F. G.; Bourhis, J.; Coukos, G. Radiotherapy Combination Opportunities Leveraging Immunity for the Next Oncology Practice. Ca-Cancer J. Clin. 2017, 67, 65−85. (486) Zhang, C.; Zhao, K.; Bu, W.; Ni, D.; Liu, Y.; Feng, J.; Shi, J. Marriage of Scintillator and Semiconductor for Synchronous Radiotherapy and Deep Photodynamic Therapy with Diminished Oxygen Dependence. Angew. Chem., Int. Ed. 2015, 54, 1770−1774. (487) Xu, L. G.; Cheng, L.; Wang, C.; Peng, R.; Liu, Z. Conjugated Polymers for Photothermal Therapy of Cancer. Polym. Chem. 2014, 5, 1573−1580. (488) Yin, W.; Yan, L.; Yu, J.; Tian, G.; Zhou, L.; Zheng, X.; Zhang, X.; Yong, Y.; Li, J.; Gu, Z.; et al. High-Throughput Synthesis of SingleLayer MoS2 Nanosheets as a near-Infrared Photothermal-Triggered Drug Delivery for Effective Cancer Therapy. ACS Nano 2014, 8, 6922−6933. CR


Chemical Reviews

Review

(489) Shibu, E. S.; Hamada, M.; Murase, N.; Biju, V. Nanomaterials Formulations for Photothermal and Photodynamic Therapy of Cancer. J. Photochem. Photobiol., C 2013, 15, 53−72. (490) Lal, S.; Clare, S. E.; Halas, N. J. Nanoshell-Enabled Photothermal Cancer Therapy: Impending Clinical Impact. Acc. Chem. Res. 2008, 41, 1842−1851. (491) Yang, K.; Xu, H.; Cheng, L.; Sun, C.; Wang, J.; Liu, Z. In Vitro and in Vivo near-Infrared Photothermal Therapy of Cancer Using Polypyrrole Organic Nanoparticles. Adv. Mater. 2012, 24, 5586−5592. (492) Shao, J.; Ruan, C.; Xie, H.; Li, Z.; Wang, H.; Chu, P. K.; Yu, X. F. Black-Phosphorus-Incorporated Hydrogel as a Sprayable and Biodegradable Photothermal Platform for Postsurgical Treatment of Cancer. Adv. Sci. 2018, 5, 1700848. (493) Lin, H.; Wang, X.; Yu, L.; Chen, Y.; Shi, J. Two-Dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion. Nano Lett. 2017, 17, 384−391. (494) Dai, C.; Chen, Y.; Jing, X.; Xiang, L.; Yang, D.; Lin, H.; Liu, Z.; Han, X.; Wu, R. Two-Dimensional Tantalum Carbide (MXenes) Composite Nanosheets for Multiple Imaging-Guided Photothermal Tumor Ablation. ACS Nano 2017, 11, 12696−12712. (495) Dong, W.; Li, Y.; Niu, D.; Ma, Z.; Gu, J.; Chen, Y.; Zhao, W.; Liu, X.; Liu, C.; Shi, J. Facile Synthesis of Monodisperse Superparamagnetic Fe3O4 Core@Hybrid@Au Shell Nanocomposite for Bimodal Imaging and Photothermal Therapy. Adv. Mater. 2011, 23, 5392−5397. (496) Wang, Y.; Wang, K.; Zhao, J.; Liu, X.; Bu, J.; Yan, X.; Huang, R. Multifunctional Mesoporous Silica-Coated Graphene Nanosheet Used for Chemo-Photothermal Synergistic Targeted Therapy of Glioma. J. Am. Chem. Soc. 2013, 135, 4799−4804. (497) Liu, J.; Liang, H.; Li, M.; Luo, Z.; Zhang, J.; Guo, X.; Cai, K. Tumor Acidity Activating Multifunctional Nanoplatform for NIRMediated Multiple Enhanced Photodynamic and Photothermal Tumor Therapy. Biomaterials 2018, 157, 107−124. (498) Xing, R.; Liu, K.; Jiao, T.; Zhang, N.; Ma, K.; Zhang, R.; Zou, Q.; Ma, G.; Yan, X. An Injectable Self-Assembling Collagen-Gold Hybrid Hydrogel for Combinatorial Antitumor Photothermal/Photodynamic Therapy. Adv. Mater. 2016, 28, 3669−3676. (499) Yang, D.; Yang, G. X.; Yang, P. P.; Lv, R. C.; Gai, S. L.; Li, C. X.; He, F.; Lin, J. Assembly of Au Plasmonic Photothermal Agent and Iron Oxide Nanoparticles on Ultrathin Black Phosphorus for Targeted Photothermal and Photodynamic Cancer Therapy. Adv. Funct. Mater. 2017, 27, 1700371. (500) Melamed, J. R.; Edelstein, R. S.; Day, E. S. Elucidating the Fundamental Mechanisms of Cell Death Triggered by Photothermal Therapy. ACS Nano 2015, 9, 6−11. (501) Zhang, L.; Wang, D.; Yang, K.; Sheng, D.; Tan, B.; Wang, Z.; Ran, H.; Yi, H.; Zhong, Y.; Lin, H.; et al. Mitochondria-Targeted Artificial “Nano-RBCs” for Amplified Synergistic Cancer Phototherapy by a Single NIR Irradiation. Adv. Sci. 2018, 5, 1800049. (502) Kirkwood, J. M.; Butterfield, L. H.; Tarhini, A. A.; Zarour, H.; Kalinski, P.; Ferrone, S. Immunotherapy of Cancer in 2012. Ca-Cancer J. Clin. 2012, 62, 309−335. (503) Vanneman, M.; Dranoff, G. Combining Immunotherapy and Targeted Therapies in Cancer Treatment. Nat. Rev. Cancer 2012, 12, 237−251. (504) Melero, I.; Berman, D. M.; Aznar, M. A.; Korman, A. J.; Perez Gracia, J. L.; Haanen, J. Evolving Synergistic Combinations of Targeted Immunotherapies to Combat Cancer. Nat. Rev. Cancer 2015, 15, 457−472. (505) Chiang, C. S.; Lin, Y. J.; Lee, R.; Lai, Y. H.; Cheng, H. W.; Hsieh, C. H.; Shyu, W. C.; Chen, S. Y. Combination of FucoidanBased Magnetic Nanoparticles and Immunomodulators Enhances Tumour-Localized Immunotherapy. Nat. Nanotechnol. 2018, 13, 746− 754. (506) Li, A. W.; Sobral, M. C.; Badrinath, S.; Choi, Y.; Graveline, A.; Stafford, A. G.; Weaver, J. C.; Dellacherie, M. O.; Shih, T. Y.; Ali, O. A.; et al. A Facile Approach to Enhance Antigen Response for Personalized Cancer Vaccination. Nat. Mater. 2018, 17, 528−534.

(507) Zhang, Y.; Li, N.; Suh, H.; Irvine, D. J. Nanoparticle Anchoring Targets Immune Agonists to Tumors Enabling Anti-Cancer Immunity without Systemic Toxicity. Nat. Commun. 2018, 9, 6. (508) Chen, Q.; Xu, L.; Liang, C.; Wang, C.; Peng, R.; Liu, Z. Photothermal Therapy with Immune-Adjuvant Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy. Nat. Commun. 2016, 7, 13193. (509) Pan, J.; Wang, Y.; Zhang, C.; Wang, X.; Wang, H.; Wang, J.; Yuan, Y.; Wang, X.; Zhang, X.; Yu, C.; et al. Antigen-Directed Fabrication of a Multifunctional Nanovaccine with Ultrahigh Antigen Loading Efficiency for Tumor Photothermal-Immunotherapy. Adv. Mater. 2018, 30, 1704408. (510) Yang, Y.; Tang, J.; Abbaraju, P. L.; Jambhrunkar, M.; Song, H.; Zhang, M.; Lei, C.; Fu, J.; Gu, Z.; Liu, Y.; et al. Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-Immunotherapy. Angew. Chem., Int. Ed. 2018, 57, 11764− 11769. (511) Oberli, M. A.; Reichmuth, A. M.; Dorkin, J. R.; Mitchell, M. J.; Fenton, O. S.; Jaklenec, A.; Anderson, D. G.; Langer, R.; Blankschtein, D. Lipid Nanoparticle Assisted MRNA Delivery for Potent Cancer Immunotherapy. Nano Lett. 2017, 17, 1326−1335. (512) Song, W.; Musetti, S. N.; Huang, L. Nanomaterials for Cancer Immunotherapy. Biomaterials 2017, 148, 16−30. (513) He, Q.; Guo, S.; Qian, Z.; Chen, X. Development of Individualized Anti-Metastasis Strategies by Engineering Nanomedicines. Chem. Soc. Rev. 2015, 44, 6258−6286. (514) Kleinovink, J. W.; van Driel, P. B.; Snoeks, T. J.; Prokopi, N.; Fransen, M. F.; Cruz, L. J.; Mezzanotte, L.; Chan, A.; Lowik, C. W.; Ossendorp, F. Combination of Photodynamic Therapy and Specific Immunotherapy Efficiently Eradicates Established Tumors. Clin. Cancer Res. 2016, 22, 1459−1468. (515) Xu, J.; Xu, L.; Wang, C.; Yang, R.; Zhuang, Q.; Han, X.; Dong, Z.; Zhu, W.; Peng, R.; Liu, Z. Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer. ACS Nano 2017, 11, 4463−4474. (516) Song, W.; Kuang, J.; Li, C. X.; Zhang, M.; Zheng, D.; Zeng, X.; Liu, C.; Zhang, X. Z. Enhanced Immunotherapy Based on Photodynamic Therapy for Both Primary and Lung Metastasis Tumor Eradication. ACS Nano 2018, 12, 1978−1989. (517) Zhao, N.; Wu, B.; Hu, X.; Xing, D. NIR-Triggered HighEfficient Photodynamic and Chemo-Cascade Therapy Using Caspase3 Responsive Functionalized Upconversion Nanoparticles. Biomaterials 2017, 141, 40−49. (518) Spring, B. Q.; Bryan Sears, R.; Zheng, L. Z.; Mai, Z.; Watanabe, R.; Sherwood, M. E.; Schoenfeld, D. A.; Pogue, B. W.; Pereira, S. P.; Villa, E.; et al. A Photoactivable Multi-Inhibitor Nanoliposome for Tumour Control and Simultaneous Inhibition of Treatment Escape Pathways. Nat. Nanotechnol. 2016, 11, 378−387. (519) Yang, G. B.; Sun, X. Q.; Liu, J. J.; Feng, L. Z.; Liu, Z. LightResponsive, Singlet-Oxygen-Triggered on-Demand Drug Release from Photosensitizer-Doped Mesoporous Silica Nanorods for Cancer Combination Therapy. Adv. Funct. Mater. 2016, 26, 4722−4732. (520) Saravanakumar, G.; Lee, J.; Kim, J.; Kim, W. J. Visible LightInduced Singlet Oxygen-Mediated Intracellular Disassembly of Polymeric Micelles Co-Loaded with a Photosensitizer and an Anticancer Drug for Enhanced Photodynamic Therapy. Chem. Commun. 2015, 51, 9995−9998. (521) Lee, J.; Lee, Y. M.; Kim, J.; Kim, W. J. Doxorubicin/Ce6Loaded Nanoparticle Coated with Polymer Via Singlet OxygenSensitive Linker for Photodynamically Assisted Chemotherapy. Nanotheranostics 2017, 1, 196−207. (522) Chu, C.; Lin, H.; Liu, H.; Wang, X.; Wang, J.; Zhang, P.; Gao, H.; Huang, C.; Zeng, Y.; Tan, Y.; et al. Tumor MicroenvironmentTriggered Supramolecular System as an in Situ Nanotheranostic Generator for Cancer Phototherapy. Adv. Mater. 2017, 29, 1605928. (523) Fan, W.; Bu, W.; Shen, B.; He, Q.; Cui, Z.; Liu, Y.; Zheng, X.; Zhao, K.; Shi, J. Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent PH-/H2O2-Responsive CS


Chemical Reviews

Review

UCL Imaging and Oxygen-Elevated Synergetic Therapy. Adv. Mater. 2015, 27, 4155−4161. (524) Chen, Q.; Feng, L.; Liu, J.; Zhu, W.; Dong, Z.; Wu, Y.; Liu, Z. Intelligent Albumin-MnO2 Nanoparticles as PH-/H2O2-Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Adv. Mater. 2016, 28, 7129−7136. (525) Yao, C.; Wang, W.; Wang, P.; Zhao, M.; Li, X.; Zhang, F. NearInfrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent PH-/H2O2-Responsive O2-Evolving Synergetic Cancer Therapy. Adv. Mater. 2018, 30, 1704833. (526) Xu, Z. Y.; Wang, K.; Li, X. Q.; Chen, S.; Deng, J. M.; Cheng, Y.; Wang, Z. G. The ABCG2 Transporter Is a Key Molecular Determinant of the Efficacy of Sonodynamic Therapy with Photofrin in Glioma Stem-Like Cells. Ultrasonics 2013, 53, 232−238. (527) Wan, G. Y.; Liu, Y.; Shi, S. R.; Chen, B. W.; Wang, Y.; Wang, H. M.; Zhang, L. Y.; Zhang, N.; Wang, Y. S. Hematoporphyrin and Doxorubicin Co-Loaded Nanomicelles for the Reversal of Drug Resistance in Human Breast Cancer Cells by Combining Sonodynamic Therapy and Chemotherapy. RSC Adv. 2016, 6, 100361−100372. (528) Liu, Y.; Wan, G. Y.; Guo, H.; Liu, Y. Y.; Zhou, P.; Wang, H. M.; Wang, D.; Zhang, S. P.; Wang, Y. S.; Zhang, N. A Multifunctional Nanoparticle System Combines Sonodynamic Therapy and Chemotherapy to Treat Hepatocellular Carcinoma. Nano Res. 2017, 10, 834− 855. (529) Maluccio, M.; Covey, A. Recent Progress in Understanding, Diagnosing, and Treating Hepatocellular Carcinoma. Ca-Cancer J. Clin. 2012, 62, 394−399. (530) Feng, Q.; Zhang, W.; Yang, X.; Li, Y.; Hao, Y.; Zhang, H.; Hou, L.; Zhang, Z. PH/Ultrasound Dual-Responsive Gas Generator for Ultrasound Imaging-Guided Therapeutic Inertial Cavitation and Sonodynamic Therapy. Adv. Healthcare Mater. 2018, 7, 1700957. (531) Fan, W.; Shen, B.; Bu, W.; Zheng, X.; He, Q.; Cui, Z.; Zhao, K.; Zhang, S.; Shi, J. Design of an Intelligent Sub-50 nm NuclearTargeting Nanotheranostic System for Imaging Guided Intranuclear Radiosensitization. Chem. Sci. 2015, 6, 1747−1753. (532) Lu, N.; Fan, W.; Yi, X.; Wang, S.; Wang, Z.; Tian, R.; Jacobson, O.; Liu, Y.; Yung, B. C.; Zhang, G.; et al. Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Mild HyperthermiaInduced Bubble-Enhanced Oxygen-Sensitized Radiotherapy. ACS Nano 2018, 12, 1580−1591. (533) Mou, J.; Li, P.; Liu, C.; Xu, H.; Song, L.; Wang, J.; Zhang, K.; Chen, Y.; Shi, J.; Chen, H. Ultrasmall Cu2‑xS Nanodots for Highly Efficient Photoacoustic Imaging-Guided Photothermal Therapy. Small 2015, 11, 2275−2283. (534) Wu, L.; Wu, M.; Zeng, Y.; Zhang, D.; Zheng, A.; Liu, X.; Liu, J. Multifunctional Peg Modified Dox Loaded Mesoporous Silica Nanoparticle@CuS Nanohybrids as Photo-Thermal Agent and Thermal-Triggered Drug Release Vehicle for Hepatocellular Carcinoma Treatment. Nanotechnology 2015, 26, 025102. (535) Gao, W.; Sun, Y.; Cai, M.; Zhao, Y.; Cao, W.; Liu, Z.; Cui, G.; Tang, B. Copper Sulfide Nanoparticles as a Photothermal Switch for Trpv1 Signaling to Attenuate Atherosclerosis. Nat. Commun. 2018, 9, 231. (536) Demaria, S.; Coleman, C. N.; Formenti, S. C. Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer 2016, 2, 286− 294. (537) Formenti, S. C.; Demaria, S. Systemic Effects of Local Radiotherapy. Lancet Oncol. 2009, 10, 718−726. (538) Barker, H. E.; Paget, J. T.; Khan, A. A.; Harrington, K. J. The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence. Nat. Rev. Cancer 2015, 15, 409−425. (539) Ni, K.; Lan, G.; Chan, C.; Quigley, B.; Lu, K.; Aung, T.; Guo, N.; La Riviere, P.; Weichselbaum, R. R.; Lin, W. Nanoscale MetalOrganic Frameworks Enhance Radiotherapy to Potentiate Checkpoint Blockade Immunotherapy. Nat. Commun. 2018, 9, 2351. (540) Chao, Y.; Xu, L. G.; Liang, C.; Feng, L. Z.; Xu, J.; Dong, Z. L.; Tian, L. L.; Yi, X.; Yang, K.; Liu, Z. Combined Local Immunostimulatory Radioisotope Therapy and Systemic Immune

Checkpoint Blockade Imparts Potent Antitumour Responses. Nat. Biomed. Eng. 2018, 2, 611−621. (541) Giannakis, S.; Lopez, M. I. P.; Spuhler, D.; Perez, J. A. S.; Ibanez, P. F.; Pulgarin, C. Solar Disinfection Is an Augmentable, in Situ-Generated Photo-Fenton Reaction-Part 1: A Review of the Mechanisms and the Fundamental Aspects of the Process. Appl. Catal., B 2016, 199, 199−223. (542) Tang, Z.; Zhang, H.; Liu, Y.; Ni, D.; Zhang, H.; Zhang, J.; Yao, Z.; He, M.; Shi, J.; Bu, W. Antiferromagnetic Pyrite as the Tumor Microenvironment-Mediated Nanoplatform for Self-Enhanced Tumor Imaging and Therapy. Adv. Mater. 2017, 29, 1701683. (543) Zanganeh, S.; Hutter, G.; Spitler, R.; Lenkov, O.; Mahmoudi, M.; Shaw, A.; Pajarinen, J. S.; Nejadnik, H.; Goodman, S.; Moseley, M.; et al. Iron Oxide Nanoparticles Inhibit Tumour Growth by Inducing Pro-Inflammatory Macrophage Polarization in Tumour Tissues. Nat. Nanotechnol. 2016, 11, 986−994. (544) Sun, Q.; Zhou, Z.; Qiu, N.; Shen, Y. Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization. Adv. Mater. 2017, 29, 1606628. (545) Andersen, J. K. Oxidative Stress in Neurodegeneration: Cause or Consequence? Nat. Rev. Neurosci. 2004, 10, S18−S25. (546) Knott, A. B.; Perkins, G.; Schwarzenbacher, R.; Bossy-Wetzel, E. Mitochondrial Fragmentation in Neurodegeneration. Nat. Rev. Neurosci. 2008, 9, 505−518. (547) Block, M. L.; Zecca, L.; Hong, J. S. Microglia-Mediated Neurotoxicity: Uncovering the Molecular Mechanisms. Nat. Rev. Neurosci. 2007, 8, 57−69. (548) Busciglio, J.; Yankner, B. A. Apoptosis and Increased Generation of Reactive Oxygen Species in Down’s Syndrome Neurons in Vitro. Nature 1995, 378, 776−779. (549) Yan, S. D.; Yan, S. F.; Chen, X.; Fu, J.; Chen, M.; Kuppusamy, P.; Smith, M. A.; Perry, G.; Godman, G. C.; Nawroth, P.; et al. Nonenzymatically Glycated-Tau in Alzheimers-Disease Induces Neuronal Oxidant Stress Resulting in Cytokine Gene-Expression and Release of Amyloid Beta-Peptide. Nat. Med. 1995, 1, 693−699. (550) Coyle, J. T.; Puttfarcken, P. Oxidative Stress, Glutamate, and Neurodegenerative Disorders. Science 1993, 262, 689−695. (551) St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J. M.; Rhee, J.; Jager, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; et al. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. Cell 2006, 127, 397−408. (552) Betjes, M. G. Immune Cell Dysfunction and Inflammation in End-Stage Renal Disease. Nat. Rev. Nephrol. 2013, 9, 255−265. (553) Eming, S. A.; Wynn, T. A.; Martin, P. Inflammation and Metabolism in Tissue Repair and Regeneration. Science 2017, 356, 1026−1030. (554) Zhou, R.; Yazdi, A. S.; Menu, P.; Tschopp, J. A Role for Mitochondria in NLRP3 Inflammasome Activation. Nature 2011, 469, 221−225. (555) Ferrucci, L.; Fabbri, E. Inflammageing: Chronic Inflammation in Ageing, Cardiovascular Disease, and Frailty. Nat. Rev. Cardiol. 2018, 15, 505−522. (556) Reuter, S.; Gupta, S. C.; Chaturvedi, M. M.; Aggarwal, B. B. Oxidative Stress, Inflammation, and Cancer: How Are They Linked? Free Radical Biol. Med. 2010, 49, 1603−1616. (557) Forstermann, U. Oxidative Stress in Vascular Disease: Causes, Defense Mechanisms and Potential Therapies. Nat. Clin. Pract. Cardiovasc. Med. 2008, 5, 338−349. (558) Rajagopalan, S.; Meng, X. P.; Ramasamy, S.; Harrison, D. G.; Galis, Z. S. Reactive Oxygen Species Produced by MacrophageDerived Foam Cells Regulate the Activity of Vascular Matrix Metalloproteinases in Vitro. Implications for Atherosclerotic Plaque Stability. J. Clin. Invest. 1996, 98, 2572−2579. (559) Dhalla, N. S.; Temsah, R. M.; Netticadan, T. Role of Oxidative Stress in Cardiovascular Diseases. J. Hypertens. 2000, 18, 655−673. (560) Chouchani, E. T.; Pell, V. R.; Gaude, E.; Aksentijevic, D.; Sundier, S. Y.; Robb, E. L.; Logan, A.; Nadtochiy, S. M.; Ord, E. N. J.; Smith, A. C.; et al. Ischaemic Accumulation of Succinate Controls CT


Chemical Reviews

Review

Reperfusion Injury through Mitochondrial ROS. Nature 2014, 515, 431−435. (561) Ezraty, B.; Gennaris, A.; Barras, F.; Collet, J. F. Oxidative Stress, Protein Damage and Repair in Bacteria. Nat. Rev. Microbiol. 2017, 15, 385−396. (562) Zengler, K.; Zaramela, L. S. The Social Network of Microorganisms - How Auxotrophies Shape Complex Communities. Nat. Rev. Microbiol. 2018, 16, 383−390. (563) Miller, K. P.; Wang, L.; Benicewicz, B. C.; Decho, A. W. Inorganic Nanoparticles Engineered to Attack Bacteria. Chem. Soc. Rev. 2015, 44, 7787−7807. (564) Jiang, N.; Tan, N. S.; Ho, B.; Ding, J. L. Respiratory ProteinGenerated Reactive Oxygen Species as an Antimicrobial Strategy. Nat. Immunol. 2007, 8, 1114−1122. (565) Hong, Y.; Li, L.; Luan, G.; Drlica, K.; Zhao, X. Contribution of Reactive Oxygen Species to Thymineless Death in Escherichia Coli. Nat. Microbiol. 2017, 2, 1667−1675. (566) Brynildsen, M. P.; Winkler, J. A.; Spina, C. S.; MacDonald, I. C.; Collins, J. J. Potentiating Antibacterial Activity by Predictably Enhancing Endogenous Microbial ROS Production. Nat. Biotechnol. 2013, 31, 160−165. (567) Finkel, T. Radical Medicine: Treating Ageing to Cure Disease. Nat. Rev. Mol. Cell Biol. 2005, 6, 971−976. (568) Lopez-Otin, C.; Blasco, M. A.; Partridge, L.; Serrano, M.; Kroemer, G. The Hallmarks of Aging. Cell 2013, 153, 1194−1217. (569) Behl, C.; Davis, J. B.; Lesley, R.; Schubert, D. Hydrogen Peroxide Mediates Amyloid Beta Protein Toxicity. Cell 1994, 77, 817− 827. (570) Smith, M. A.; Sayre, L. M.; Anderson, V. E.; Harris, P. L.; Beal, M. F.; Kowall, N.; Perry, G. Cytochemical Demonstration of Oxidative Damage in Alzheimer Disease by Immunochemical Enhancement of the Carbonyl Reaction with 2,4-Dinitrophenylhydrazine. J. Histochem. Cytochem. 1998, 46, 731−735. (571) Huang, X.; Atwood, C. S.; Hartshorn, M. A.; Multhaup, G.; Goldstein, L. E.; Scarpa, R. C.; Cuajungco, M. P.; Gray, D. N.; Lim, J.; Moir, R. D.; et al. The a Beta Peptide of Alzheimer’s Disease Directly Produces Hydrogen Peroxide through Metal Ion Reduction. Biochemistry 1999, 38, 7609−7616. (572) LaFerla, F. M. Calcium Dyshomeostasis and Intracellular Signalling in Alzheimer’s Disease. Nat. Rev. Neurosci. 2002, 3, 862− 872. (573) Savelieff, M. G.; Nam, G.; Kang, J.; Lee, H. J.; Lee, M.; Lim, M. H. Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade. Chem. Rev. 2019, 119, 1221. (574) Gaggelli, E.; Kozlowski, H.; Valensin, D.; Valensin, G. Copper Homeostasis and Neurodegenerative Disorders (Alzheimer’s, Prion, and Parkinson’s Diseases and Amyotrophic Lateral Sclerosis). Chem. Rev. 2006, 106, 1995−2044. (575) Bush, A. I. The Metallobiology of Alzheimer’s Disease. Trends Neurosci. 2003, 26, 207−214. (576) Smith, M. A.; Harris, P. L. R.; Sayre, L. M.; Perry, G. Iron Accumulation in Alzheimer Disease Is a Source of Redox-Generated Free Radicals. Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 9866−9868. (577) Sayre, L. M.; Perry, G.; Harris, P. L.; Liu, Y.; Schubert, K. A.; Smith, M. A. In Situ Oxidative Catalysis by Neurofibrillary Tangles and Senile Plaques in Alzheimer’s Disease: A Central Role for Bound Transition Metals. J. Neurochem. 2000, 74, 270−279. (578) Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R. Copper, Iron and Zinc in Alzheimer’s Disease Senile Plaques. J. Neurol. Sci. 1998, 158, 47−52. (579) Kepp, K. P. Bioinorganic Chemistry of Alzheimer’s Disease. Chem. Rev. 2012, 112, 5193−5239. (580) Ni, J.; Taniguchi, A.; Ozawa, S.; Hori, Y.; Kuninobu, Y.; Saito, T.; Saido, T. C.; Tomita, T.; Sohma, Y.; Kanai, M. Near-Infrared Photoactivatable Oxygenation Catalysts of Amyloid Peptide. Chem. 2018, 4, 807−820.

(581) Curtain, C. C.; Ali, F.; Volitakis, I.; Cherny, R. A.; Norton, R. S.; Beyreuther, K.; Barrow, C. J.; Masters, C. L.; Bush, A. I.; Barnham, K. J. Alzheimer’s Disease Amyloid-Beta Binds Copper and Zinc to Generate an Allosterically Ordered Membrane-Penetrating Structure Containing Superoxide Dismutase-Like Subunits. J. Biol. Chem. 2001, 276, 20466−20473. (582) Curtain, C. C.; Ali, F. E.; Smith, D. G.; Bush, A. I.; Masters, C. L.; Barnham, K. J. Metal Ions, PH, and Cholesterol Regulate the Interactions of Alzheimer’s Disease Amyloid-Beta Peptide with Membrane Lipid. J. Biol. Chem. 2003, 278, 2977−2982. (583) Huang, X. D.; Cuajungco, M. P.; Atwood, C. S.; Hartshorn, M. A.; Tyndall, J. D. A.; Hanson, G. R.; Stokes, K. C.; Leopold, M.; Multhaup, G.; Goldstein, L. E.; et al. Cu(II) Potentiation of Alzheimer a Beta Neurotoxicity - Correlation with Cell-Free Hydrogen Peroxide Production and Metal Reduction. J. Biol. Chem. 1999, 274, 37111− 37116. (584) Atwood, C. S.; Scarpa, R. C.; Huang, X. D.; Moir, R. D.; Jones, W. D.; Fairlie, D. P.; Tanzi, R. E.; Bush, A. I. Characterization of Copper Interactions with Alzheimer Amyloid Beta Peptides: Identification of an Attomolar-Affinity Copper Binding Site on Amyloid Beta 1−42. J. Neurochem. 2000, 75, 1219−1233. (585) Spillantini, M. G.; Schmidt, M. L.; Lee, V. M.; Trojanowski, J. Q.; Jakes, R.; Goedert, M. Alpha-Synuclein in Lewy Bodies. Nature 1997, 388, 839−840. (586) Xu, J.; Kao, S. Y.; Lee, F. J.; Song, W.; Jin, L. W.; Yankner, B. A. Dopamine-Dependent Neurotoxicity of Alpha-Synuclein: A Mechanism for Selective Neurodegeneration in Parkinson Disease. Nat. Med. 2002, 8, 600−606. (587) Sulzer, D.; Bogulavsky, J.; Larsen, K. E.; Behr, G.; Karatekin, E.; Kleinman, M. H.; Turro, N.; Krantz, D.; Edwards, R. H.; Greene, L. A.; et al. Neuromelanin Biosynthesis Is Driven by Excess Cytosolic Catecholamines Not Accumulated by Synaptic Vesicles. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 11869−11874. (588) Gerard, C.; Chehhal, H.; Hugel, R. P. Complexes of Iron(III) with Ligands of Biological Interest - Dopamine and 8-Hydroxyquinoline-5-Sulfonic Acid. Polyhedron 1994, 13, 541−597. (589) Double, K. L.; Gerlach, M.; Schunemann, V.; Trautwein, A. X.; Zecca, L.; Gallorini, M.; Youdim, M. B.; Riederer, P.; Ben-Shachar, D. Iron-Binding Characteristics of Neuromelanin of the Human Substantia Nigra. Biochem. Pharmacol. 2003, 66, 489−494. (590) Faucheux, B. A.; Martin, M. E.; Beaumont, C.; Hauw, J. J.; Agid, Y.; Hirsch, E. C. Neuromelanin Associated Redox-Active Iron Is Increased in the Substantia Nigra of Patients with Parkinson’s Disease. J. Neurochem. 2003, 86, 1142−1148. (591) Lotharius, J.; Barg, S.; Wiekop, P.; Lundberg, C.; Raymon, H. K.; Brundin, P. Effect of Mutant Alpha-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line. J. Biol. Chem. 2002, 277, 38884−38894. (592) Perez, R. G.; Waymire, J. C.; Lin, E.; Liu, J. J.; Guo, F.; Zigmond, M. J. A Role for Alpha-Synuclein in the Regulation of Dopamine Biosynthesis. J. Neurosci. 2002, 22, 3090−3099. (593) Bosco, D. A.; Fowler, D. M.; Zhang, Q.; Nieva, J.; Powers, E. T.; Wentworth, P., Jr.; Lerner, R. A.; Kelly, J. W. Elevated Levels of Oxidized Cholesterol Metabolites in Lewy Body Disease Brains Accelerate Alpha-Synuclein Fibrilization. Nat. Chem. Biol. 2006, 2, 249−253. (594) Lotharius, J.; Brundin, P. Impaired Dopamine Storage Resulting from Alpha-Synuclein Mutations May Contribute to the Pathogenesis of Parkinson’s Disease. Hum. Mol. Genet. 2002, 11, 2395−2407. (595) Benjamin, E. J.; Blaha, M. J.; Chiuve, S. E.; Cushman, M.; Das, S. R.; Deo, R.; de Ferranti, S. D.; Floyd, J.; Fornage, M.; Gillespie, C.; et al. Heart Disease and Stroke Statistics-2017 Update: A Report from the American Heart Association. Circulation 2017, 135, e146−e603. (596) Love, S. Oxidative Stress in Brain Ischemia. Brain Pathol. 1999, 9, 119−131. (597) Yoshitomi, T.; Nagasaki, Y. Reactive Oxygen SpeciesScavenging Nanomedicines for the Treatment of Oxidative Stress Injuries. Adv. Healthcare Mater. 2014, 3, 1149−1161. CU


Chemical Reviews

Review

(598) Broughton, B. R.; Reutens, D. C.; Sobey, C. G. Apoptotic Mechanisms after Cerebral Ischemia. Stroke 2009, 40, 331−339. (599) Furtado, D.; Bjornmalm, M.; Ayton, S.; Bush, A. I.; Kempe, K.; Caruso, F. Overcoming the Blood-Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases. Adv. Mater. 2018, 30, 1801362. (600) Hu, B.; Dai, F.; Fan, Z.; Ma, G.; Tang, Q.; Zhang, X. Nanotheranostics: Congo Red/Rutin-MNPs with Enhanced Magnetic Resonance Imaging and H2O2-Responsive Therapy of Alzheimer’s Disease in APPswe/PS1dE9 Transgenic Mice. Adv. Mater. 2015, 27, 5499−5505. (601) Obermeier, B.; Daneman, R.; Ransohoff, R. M. Development, Maintenance and Disruption of the Blood-Brain Barrier. Nat. Med. 2013, 19, 1584−1596. (602) Lv, W.; Xu, J.; Wang, X.; Li, X.; Xu, Q.; Xin, H. Bioengineered Boronic Ester Modified Dextran Polymer Nanoparticles as Reactive Oxygen Species Responsive Nanocarrier for Ischemic Stroke Treatment. ACS Nano 2018, 12, 5417−5426. (603) Fang, R. H.; Kroll, A. V.; Gao, W.; Zhang, L. Cell Membrane Coating Nanotechnology. Adv. Mater. 2018, 30, 1706759. (604) Xu, C.; Qu, X. G. Cerium Oxide Nanoparticle: A Remarkably Versatile Rare Earth Nanomaterial for Biological Applications. NPG Asia Mater. 2014, 6, e90. (605) Kwon, H. J.; Kim, D.; Seo, K.; Kim, Y. G.; Han, S. I.; Kang, T.; Soh, M.; Hyeon, T. Ceria Nanoparticle Systems for Selective Scavenging of Mitochondrial, Intracellular, and Extracellular Reactive Oxygen Species in Parkinson’s Disease. Angew. Chem., Int. Ed. 2018, 57, 9408−9412. (606) Schubert, D.; Dargusch, R.; Raitano, J.; Chan, S. W. Cerium and Yttrium Oxide Nanoparticles Are Neuroprotective. Biochem. Biophys. Res. Commun. 2006, 342, 86−91. (607) Kim, C. K.; Kim, T.; Choi, I. Y.; Soh, M.; Kim, D.; Kim, Y. J.; Jang, H.; Yang, H. S.; Kim, J. Y.; Park, H. K.; et al. Ceria Nanoparticles That Can Protect against Ischemic Stroke. Angew. Chem., Int. Ed. 2012, 51, 11039−11043. (608) Bao, Q.; Hu, P.; Xu, Y.; Cheng, T.; Wei, C.; Pan, L.; Shi, J. Simultaneous Blood-Brain Barrier Crossing and Protection for Stroke Treatment Based on Edaravone-Loaded Ceria Nanoparticles. ACS Nano 2018, 12, 6794−6805. (609) Kwon, H. J.; Cha, M. Y.; Kim, D.; Kim, D. K.; Soh, M.; Shin, K.; Hyeon, T.; Mook-Jung, I. Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease. ACS Nano 2016, 10, 2860−2870. (610) Roberson, E. D.; Scearce-Levie, K.; Palop, J. J.; Yan, F.; Cheng, I. H.; Wu, T.; Gerstein, H.; Yu, G. Q.; Mucke, L. Reducing Endogenous Tau Ameliorates Amyloid Beta-Induced Deficits in an Alzheimer’s Disease Mouse Model. Science 2007, 316, 750−754. (611) Giacobini, E.; Gold, G. Alzheimer Disease Therapy–Moving from Amyloid-Beta to Tau. Nat. Rev. Neurol. 2013, 9, 677−686. (612) Verwilst, P.; Kim, H. S.; Kim, S.; Kang, C.; Kim, J. S. Shedding Light on Tau Protein Aggregation: The Progress in Developing Highly Selective Fluorophores. Chem. Soc. Rev. 2018, 47, 2249−2265. (613) Chen, Q.; Du, Y.; Zhang, K.; Liang, Z.; Li, J.; Yu, H.; Ren, R.; Feng, J.; Jin, Z.; Li, F.; et al. Tau-Targeted Multifunctional Nanocomposite for Combinational Therapy of Alzheimer’s Disease. ACS Nano 2018, 12, 1321−1338. (614) Zeng, F.; Wu, Y.; Li, X.; Ge, X.; Guo, Q.; Lou, X.; Cao, Z.; Hu, B.; Long, N. J.; Mao, Y.; et al. Custom-Made Ceria Nanoparticles Show a Neuroprotective Effect by Modulating Phenotypic Polarization of the Microglia. Angew. Chem., Int. Ed. 2018, 57, 5808−5812. (615) Zhang, Y.; Wang, Z.; Li, X.; Wang, L.; Yin, M.; Wang, L.; Chen, N.; Fan, C.; Song, H. Dietary Iron Oxide Nanoparticles Delay Aging and Ameliorate Neurodegeneration in Drosophila. Adv. Mater. 2016, 28, 1387−1393. (616) Ren, C.; Hu, X.; Zhou, Q. Graphene Oxide Quantum Dots Reduce Oxidative Stress and Inhibit Neurotoxicity in Vitro and in Vivo through Catalase-Like Activity and Metabolic Regulation. Adv. Sci. 2018, 5, 1700595.

(617) Reddy, M. K.; Wu, L.; Kou, W.; Ghorpade, A.; Labhasetwar, V. Superoxide Dismutase-Loaded PLGA Nanoparticles Protect Cultured Human Neurons under Oxidative Stress. Appl. Biochem. Biotechnol. 2008, 151, 565−577. (618) Yang, B.; Chen, Y.; Shi, J. Exosome Biochemistry and Advanced Nanotechnology for Next-Generation Theranostic Platforms. Adv. Mater. 2019, 31, 1802896. (619) He, C.; Zheng, S.; Luo, Y.; Wang, B. Exosome Theranostics: Biology and Translational Medicine. Theranostics 2018, 8, 237−255. (620) Xu, R.; Rai, A.; Chen, M.; Suwakulsiri, W.; Greening, D. W.; Simpson, R. J. Extracellular Vesicles in Cancer - Implications for Future Improvements in Cancer Care. Nat. Rev. Clin. Oncol. 2018, 15, 617−638. (621) Thery, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, Biogenesis and Function. Nat. Rev. Immunol. 2002, 2, 569−579. (622) El Andaloussi, S.; Mager, I.; Breakefield, X. O.; Wood, M. J. Extracellular Vesicles: Biology and Emerging Therapeutic Opportunities. Nat. Rev. Drug Discovery 2013, 12, 347−357. (623) van Niel, G.; D’Angelo, G.; Raposo, G. Shedding Light on the Cell Biology of Extracellular Vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213−228. (624) Armstrong, J. P. K.; Holme, M. N.; Stevens, M. M. ReEngineering Extracellular Vesicles as Smart Nanoscale Therapeutics. ACS Nano 2017, 11, 69−83. (625) Tan, A.; Rajadas, J.; Seifalian, A. M. Exosomes as NanoTheranostic Delivery Platforms for Gene Therapy. Adv. Drug Delivery Rev. 2013, 65, 357−367. (626) Kojima, R.; Bojar, D.; Rizzi, G.; Hamri, G. C.; El-Baba, M. D.; Saxena, P.; Auslander, S.; Tan, K. R.; Fussenegger, M. Designer Exosomes Produced by Implanted Cells Intracerebrally Deliver Therapeutic Cargo for Parkinson’s Disease Treatment. Nat. Commun. 2018, 9, 1305. (627) Liu, Y.; Ai, K.; Ji, X.; Askhatova, D.; Du, R.; Lu, L.; Shi, J. Comprehensive Insights into the Multi-Antioxidative Mechanisms of Melanin Nanoparticles and Their Application to Protect Brain from Injury in Ischemic Stroke. J. Am. Chem. Soc. 2017, 139, 856−862. (628) Cui, Z.; Bu, W.; Fan, W.; Zhang, J.; Ni, D.; Liu, Y.; Wang, J.; Liu, J.; Yao, Z.; Shi, J. Sensitive Imaging and Effective Capture of Cu2+: Towards Highly Efficient Theranostics of Alzheimer’s Disease. Biomaterials 2016, 104, 158−167. (629) Gao, N.; Dong, K.; Zhao, A. D.; Sun, H. J.; Wang, Y.; Ren, J. S.; Qu, X. G. Polyoxometalate-Based Nanozyme: Design of a Multifunctional Enzyme for Multi-Faceted Treatment of Alzheimer’s Disease. Nano Res. 2016, 9, 1079−1090. (630) Chen, Y.; Tan, C.; Zhang, H.; Wang, L. Two-Dimensional Graphene Analogues for Biomedical Applications. Chem. Soc. Rev. 2015, 44, 2681−2701. (631) Kong, X.; Liu, Q.; Zhang, C.; Peng, Z.; Chen, Q. Elemental Two-Dimensional Nanosheets Beyond Graphene. Chem. Soc. Rev. 2017, 46, 2127−2157. (632) Manzeli, S.; Ovchinnikov, D.; Pasquier, D.; Yazyev, O. V.; Kis, A. 2D Transition Metal Dichalcogenides. Nat. Rev. Mater. 2017, 2, 17033. (633) Kurapati, R.; Kostarelos, K.; Prato, M.; Bianco, A. Biomedical Uses for 2D Materials Beyond Graphene: Current Advances and Challenges Ahead. Adv. Mater. 2016, 28, 6052−6074. (634) Ling, X.; Wang, H.; Huang, S.; Xia, F.; Dresselhaus, M. S. The Renaissance of Black Phosphorus. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 4523−4530. (635) Chen, W.; Ouyang, J.; Yi, X.; Xu, Y.; Niu, C.; Zhang, W.; Wang, L.; Sheng, J.; Deng, L.; Liu, Y. N.; et al. Black Phosphorus Nanosheets as a Neuroprotective Nanomedicine for Neurodegenerative Disorder Therapy. Adv. Mater. 2018, 30, 1703458. (636) Hotamisligil, G. S. Inflammation and Metabolic Disorders. Nature 2006, 444, 860−867. (637) Zhang, K.; Kaufman, R. J. From Endoplasmic-Reticulum Stress to the Inflammatory Response. Nature 2008, 454, 455−462. CV


Chemical Reviews

Review

(638) Charo, I. F.; Ransohoff, R. M. The Many Roles of Chemokines and Chemokine Receptors in Inflammation. N. Engl. J. Med. 2006, 354, 610−621. (639) Hansson, G. K.; Libby, P. The Immune Response in Atherosclerosis: A Double-Edged Sword. Nat. Rev. Immunol. 2006, 6, 508−519. (640) Tu, B. P.; Weissman, J. S. The FAD- and O2-Dependent Reaction Cycle of Ero1-Mediated Oxidative Protein Folding in the Endoplasmic Reticulum. Mol. Cell 2002, 10, 983−994. (641) Cuozzo, J. W.; Kaiser, C. A. Competition between Glutathione and Protein Thiols for Disulphide-Bond Formation. Nat. Cell Biol. 1999, 1, 130−135. (642) Li, L.; Guo, J.; Wang, Y.; Xiong, X.; Tao, H.; Li, J.; Jia, Y.; Hu, H.; Zhang, J. A Broad-Spectrum ROS-Eliminating Material for Prevention of Inflammation and Drug-Induced Organ Toxicity. Adv. Sci. 2018, 5, 1800781. (643) Zhang, Q.; Tao, H.; Lin, Y.; Hu, Y.; An, H.; Zhang, D.; Feng, S.; Hu, H.; Wang, R.; Li, X.; et al. A Superoxide Dismutase/Catalase Mimetic Nanomedicine for Targeted Therapy of Inflammatory Bowel Disease. Biomaterials 2016, 105, 206−221. (644) Wang, Y.; Li, L.; Zhao, W.; Dou, Y.; An, H.; Tao, H.; Xu, X.; Jia, Y.; Lu, S.; Zhang, J.; et al. Targeted Therapy of Atherosclerosis by a Broad-Spectrum Reactive Oxygen Species Scavenging Nanoparticle with Intrinsic Anti-Inflammatory Activity. ACS Nano 2018, 12, 8943− 8960. (645) Bao, X.; Zhao, J.; Sun, J.; Hu, M.; Yang, X. Polydopamine Nanoparticles as Efficient Scavengers for Reactive Oxygen Species in Periodontal Disease. ACS Nano 2018, 12, 8882−8892. (646) Hirst, S. M.; Karakoti, A. S.; Tyler, R. D.; Sriranganathan, N.; Seal, S.; Reilly, C. M. Anti-Inflammatory Properties of Cerium Oxide Nanoparticles. Small 2009, 5, 2848−2856. (647) Soh, M.; Kang, D. W.; Jeong, H. G.; Kim, D.; Kim, D. Y.; Yang, W.; Song, C.; Baik, S.; Choi, I. Y.; Ki, S. K.; et al. Ceria-Zirconia Nanoparticles as an Enhanced Multi-Antioxidant for Sepsis Treatment. Angew. Chem., Int. Ed. 2017, 56, 11399−11403. (648) Chen, J.; Li, S.; Zhang, Y.; Wang, W.; Zhang, X.; Zhao, Y.; Wang, Y.; Bi, H. A Reloadable Self-Healing Hydrogel Enabling Diffusive Transport of C-Dots across Gel-Gel Interface for Scavenging Reactive Oxygen Species. Adv. Healthcare Mater. 2017, 6, 1700746. (649) Kang, C.; Cho, W.; Park, M.; Kim, J.; Park, S.; Shin, D.; Song, C.; Lee, D. H2O2-Triggered Bubble Generating Antioxidant Polymeric Nanoparticles as Ischemia/Reperfusion Targeted Nanotheranostics. Biomaterials 2016, 85, 195−203. (650) Chung, M. F.; Chia, W. T.; Wan, W. L.; Lin, Y. J.; Sung, H. W. Controlled Release of an Anti-Inflammatory Drug Using an Ultrasensitive ROS-Responsive Gas-Generating Carrier for Localized Inflammation Inhibition. J. Am. Chem. Soc. 2015, 137, 12462−12465. (651) Walling, C.; Kato, S. Oxidation of Alcohols by Fentons Reagent. Effect of Copper Ion. J. Am. Chem. Soc. 1971, 93, 4275− 4281. (652) Feng, S.; Hu, Y.; Peng, S.; Han, S.; Tao, H.; Zhang, Q.; Xu, X.; Zhang, J.; Hu, H. Nanoparticles Responsive to the Inflammatory Microenvironment for Targeted Treatment of Arterial Restenosis. Biomaterials 2016, 105, 167−184. (653) Howard, M. D.; Hood, E. D.; Zern, B.; Shuvaev, V. V.; Grosser, T.; Muzykantov, V. R. Nanocarriers for Vascular Delivery of AntiInflammatory Agents. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 205− 226. (654) Brito, L.; Amiji, M. Nanoparticulate Carriers for the Treatment of Coronary Restenosis. Int. J. Nanomedicine 2007, 2, 143−161. (655) Uwatoku, T.; Shimokawa, H.; Abe, K.; Matsumoto, Y.; Hattori, T.; Oi, K.; Matsuda, T.; Kataoka, K.; Takeshita, A. Application of Nanoparticle Technology for the Prevention of Restenosis after Balloon Injury in Rats. Circ. Res. 2003, 92, 62−69. (656) Peer, D.; Park, E. J.; Morishita, Y.; Carman, C. V.; Shimaoka, M. Systemic Leukocyte-Directed SiRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target. Science 2008, 319, 627−630. (657) Wilson, D. S.; Dalmasso, G.; Wang, L.; Sitaraman, S. V.; Merlin, D.; Murthy, N. Orally Delivered Thioketal Nanoparticles

Loaded with TNF-Alpha-SiRNA Target Inflammation and Inhibit Gene Expression in the Intestines. Nat. Mater. 2010, 9, 923−928. (658) Shukla, A. K.; Verma, M.; Singh, K. N. Superoxide Induced Deprotection of 1,3-Dithiolanes: A Convenient Method of Dedithioacetalization. Indian J. Chem. B 2004, 43, 1748−1752. (659) Colonna, S.; Gaggero, N.; Carrea, G.; Pasta, P. Enantio and Diastereoselectivity of Cyclohexanone Monooxygenase Catalyzed Oxidation of 1,3-Dithioacetals. Tetrahedron: Asymmetry 1996, 7, 565−570. (660) Wan, W. L.; Lin, Y. J.; Chen, H. L.; Huang, C. C.; Shih, P. C.; Bow, Y. R.; Chia, W. T.; Sung, H. W. In Situ Nanoreactor for Photosynthesizing H2 Gas to Mitigate Oxidative Stress in Tissue Inflammation. J. Am. Chem. Soc. 2017, 139, 12923−12926. (661) Berardi, S.; Drouet, S.; Francas, L.; Gimbert-Surinach, C.; Guttentag, M.; Richmond, C.; Stoll, T.; Llobet, A. Molecular Artificial Photosynthesis. Chem. Soc. Rev. 2014, 43, 7501−7519. (662) Zheng, B.; Sabatini, R. P.; Fu, W. F.; Eum, M. S.; Brennessel, W. W.; Wang, L.; McCamant, D. W.; Eisenberg, R. Light-Driven Generation of Hydrogen: New Chromophore Dyads for Increased Activity Based on Bodipy Dye and Pt(Diimine)(Dithiolate) Complexes. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 3987−3996. (663) Kurioka, T.; Matsunobu, T.; Satoh, Y.; Niwa, K.; Shiotani, A. Inhaled Hydrogen Gas Therapy for Prevention of Noise-Induced Hearing Loss through Reducing Reactive Oxygen Species. Neurosci. Res. 2014, 89, 69−74. (664) Bui, A. L.; Horwich, T. B.; Fonarow, G. C. Epidemiology and Risk Profile of Heart Failure. Nat. Rev. Cardiol. 2011, 8, 30−41. (665) Mahmoudi, M.; Yu, M.; Serpooshan, V.; Wu, J. C.; Langer, R.; Lee, R. T.; Karp, J. M.; Farokhzad, O. C. Multiscale Technologies for Treatment of Ischemic Cardiomyopathy. Nat. Nanotechnol. 2017, 12, 845−855. (666) White, H. D.; Chew, D. P. Acute Myocardial Infarction. Lancet 2008, 372, 570−584. (667) Hink, U.; Li, H.; Mollnau, H.; Oelze, M.; Matheis, E.; Hartmann, M.; Skatchkov, M.; Thaiss, F.; Stahl, R. A.; Warnholtz, A.; et al. Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus. Circ. Res. 2001, 88, 14−22. (668) Li, H. G.; Gutenberg, J.; Witte, K.; August, M.; Brausch, I.; Godtel-Armbrust, U.; Habermeier, A.; Gloss, E. I.; Oelze, M.; Munzel, T.; et al. Reversal of ENOS Uncoupling and Upregulation of ENOS Expression Lowers Blood Pressure in Spontaneously Hypertensive Rats. Circulation 2005, 112, U355−U355. (669) Warnholtz, A.; Nickenig, G.; Schulz, E.; Macharzina, R.; Brasen, J. H.; Skatchkov, M.; Heitzer, T.; Stasch, J. P.; Griendling, K. K.; Harrison, D. G.; et al. Increased NADH-Oxidase-Mediated Superoxide Production in the Early Stages of Atherosclerosis: Evidence for Involvement of the Renin-Angiotensin System. Circulation 1999, 99, 2027−2033. (670) Sorescu, D.; Weiss, D.; Lassegue, B.; Clempus, R. E.; Szocs, K.; Sorescu, G. P.; Valppu, L.; Quinn, M. T.; Lambeth, J. D.; Vega, J. D.; et al. Superoxide Production and Expression of NOX Family Proteins in Human Atherosclerosis. Circulation 2002, 105, 1429−1435. (671) Forstermann, U.; Munzel, T. Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace. Circulation 2006, 113, 1708−1714. (672) Kunsch, C.; Medford, R. M. Oxidative Stress as a Regulator of Gene Expression in the Vasculature. Circ. Res. 1999, 85, 753−766. (673) Chen, Q. Z.; Harding, S. E.; Ali, N. N.; Lyon, A. R.; Boccaccini, A. R. Biomaterials in Cardiac Tissue Engineering: Ten Years of Research Survey. Mater. Sci. Eng., R 2008, 59, 1−37. (674) Tao, G.; Kahr, P. C.; Morikawa, Y.; Zhang, M.; Rahmani, M.; Heallen, T. R.; Li, L.; Sun, Z.; Olson, E. N.; Amendt, B. A.; et al. Pitx2 Promotes Heart Repair by Activating the Antioxidant Response after Cardiac Injury. Nature 2016, 534, 119−123. (675) Orlic, D.; Kajstura, J.; Chimenti, S.; Jakoniuk, I.; Anderson, S. M.; Li, B.; Pickel, J.; McKay, R.; Nadal-Ginard, B.; Bodine, D. M.; et al. Bone Marrow Cells Regenerate Infarcted Myocardium. Nature 2001, 410, 701−705. CW


Chemical Reviews

Review

(676) Kinnaird, T.; Stabile, E.; Burnett, M. S.; Lee, C. W.; Barr, S.; Fuchs, S.; Epstein, S. E. Marrow-Derived Stromal Cells Express Genes Encoding a Broad Spectrum of Arteriogenic Cytokines and Promote in Vitro and in Vivo Arteriogenesis through Paracrine Mechanisms. Circ. Res. 2004, 94, 678−685. (677) Gnecchi, M.; He, H.; Liang, O. D.; Melo, L. G.; Morello, F.; Mu, H.; Noiseux, N.; Zhang, L.; Pratt, R. E.; Ingwall, J. S.; et al. Paracrine Action Accounts for Marked Protection of Ischemic Heart by Akt-Modified Mesenchymal Stem Cells. Nat. Med. 2005, 11, 367− 368. (678) Lee, W. Y.; Wei, H. J.; Lin, W. W.; Yeh, Y. C.; Hwang, S. M.; Wang, J. J.; Tsai, M. S.; Chang, Y.; Sung, H. W. Enhancement of Cell Retention and Functional Benefits in Myocardial Infarction Using Human Amniotic-Fluid Stem-Cell Bodies Enriched with Endogenous ECM. Biomaterials 2011, 32, 5558−5567. (679) Eltzschig, H. K.; Eckle, T. Ischemia and Reperfusion–from Mechanism to Translation. Nat. Med. 2011, 17, 1391−1401. (680) Angelos, M. G.; Kutala, V. K.; Torres, C. A.; He, G.; Stoner, J. D.; Mohammad, M.; Kuppusamy, P. Hypoxic Reperfusion of the Ischemic Heart and Oxygen Radical Generation. Am. J. Physiol. Heart Circ. Physiol. 2006, 290, 341−347. (681) Gailit, J.; Colflesh, D.; Rabiner, I.; Simone, J.; Goligorsky, M. S. Redistribution and Dysfunction of Integrins in Cultured Renal Epithelial Cells Exposed to Oxidative Stress. Am. J. Physiol. 1993, 264, 149−157. (682) Miro, P.; Audiffred, M.; Heine, T. An Atlas of TwoDimensional Materials. Chem. Soc. Rev. 2014, 43, 6537−6554. (683) Chen, Y.; Wu, Y.; Sun, B.; Liu, S.; Liu, H. Two-Dimensional Nanomaterials for Cancer Nanotheranostics. Small 2017, 13, 1603446. (684) Tang, Q.; Zhou, Z. Graphene-Analogous Low-Dimensional Materials. Prog. Mater. Sci. 2013, 58, 1244−1315. (685) Gupta, A.; Sakthivel, T.; Seal, S. Recent Development in 2D Materials Beyond Graphene. Prog. Mater. Sci. 2015, 73, 44−126. (686) Mao, H. Y.; Laurent, S.; Chen, W.; Akhavan, O.; Imani, M.; Ashkarran, A. A.; Mahmoudi, M. Graphene: Promises, Facts, Opportunities, and Challenges in Nanomedicine. Chem. Rev. 2013, 113, 3407−3424. (687) Yang, K.; Feng, L.; Shi, X.; Liu, Z. Nano-Graphene in Biomedicine: Theranostic Applications. Chem. Soc. Rev. 2013, 42, 530−547. (688) Xu, M.; Liang, T.; Shi, M.; Chen, H. Graphene-Like TwoDimensional Materials. Chem. Rev. 2013, 113, 3766−3798. (689) Feng, L.; Wu, L.; Qu, X. New Horizons for Diagnostics and Therapeutic Applications of Graphene and Graphene Oxide. Adv. Mater. 2013, 25, 168−186. (690) Yu, X. W.; Cheng, H. H.; Zhang, M.; Zhao, Y.; Qu, L. T.; Shi, G. Q. Graphene-Based Smart Materials. Nat. Rev. Mater. 2017, 2, 17046. (691) Sanchez, V. C.; Jachak, A.; Hurt, R. H.; Kane, A. B. Biological Interactions of Graphene-Family Nanomaterials: An Interdisciplinary Review. Chem. Res. Toxicol. 2012, 25, 15−34. (692) Zhou, Y.; Jing, X. X.; Chen, Y. Material Chemistry of Graphene Oxide-Based Nanocomposites for Theranostic Nanomedicine. J. Mater. Chem. B 2017, 5, 6451−6470. (693) Panda, S.; Rout, T. K.; Prusty, A. D.; Ajayan, P. M.; Nayak, S. Electron Transfer Directed Antibacterial Properties of Graphene Oxide on Metals. Adv. Mater. 2018, 30, 1702149. (694) Shi, X. T.; Chang, H. X.; Chen, S.; Lai, C.; Khademhosseini, A.; Wu, H. K. Regulating Cellular Behavior on Few-Layer Reduced Graphene Oxide Films with Well-Controlled Reduction States. Adv. Funct. Mater. 2012, 22, 751−759. (695) Park, J.; Kim, B.; Han, J.; Oh, J.; Park, S.; Ryu, S.; Jung, S.; Shin, J. Y.; Lee, B. S.; Hong, B. H.; et al. Graphene Oxide Flakes as a Cellular Adhesive: Prevention of Reactive Oxygen Species Mediated Death of Implanted Cells for Cardiac Repair. ACS Nano 2015, 9, 4987−4999. (696) Pagliari, F.; Mandoli, C.; Forte, G.; Magnani, E.; Pagliari, S.; Nardone, G.; Licoccia, S.; Minieri, M.; Di Nardo, P.; Traversa, E.

Cerium Oxide Nanoparticles Protect Cardiac Progenitor Cells from Oxidative Stress. ACS Nano 2012, 6, 3767−3775. (697) Han, J.; Kim, Y. S.; Lim, M. Y.; Kim, H. Y.; Kong, S.; Kang, M.; Choo, Y. W.; Jun, J. H.; Ryu, S.; Jeong, H. Y.; et al. Dual Roles of Graphene Oxide to Attenuate Inflammation and Elicit Timely Polarization of Macrophage Phenotypes for Cardiac Repair. ACS Nano 2018, 12, 1959−1977. (698) Frangogiannis, N. G. The Inflammatory Response in Myocardial Injury, Repair, and Remodelling. Nat. Rev. Cardiol. 2014, 11, 255−265. (699) Jeong, H. Y.; Kang, W. S.; Hong, M. H.; Jeong, H. C.; Shin, M. G.; Jeong, M. H.; Kim, Y. S.; Ahn, Y. 5-Azacytidine Modulates Interferon Regulatory Factor 1 in Macrophages to Exert a Cardioprotective Effect. Sci. Rep. 2015, 5, 15768. (700) Gombozhapova, A.; Rogovskaya, Y.; Shurupov, V.; Rebenkova, M.; Kzhyshkowska, J.; Popov, S. V.; Karpov, R. S.; Ryabov, V. Macrophage Activation and Polarization in Post-Infarction Cardiac Remodeling. J. Biomed. Sci. 2017, 24, 13. (701) Koetting, M. C.; Peters, J. T.; Steichen, S. D.; Peppas, N. A. Stimulus-Responsive Hydrogels: Theory, Modern Advances, and Applications. Mater. Sci. Eng., R 2015, 93, 1−49. (702) Li, J.; Shu, Y.; Hao, T.; Wang, Y.; Qian, Y.; Duan, C.; Sun, H.; Lin, Q.; Wang, C. A Chitosan-Glutathione Based Injectable Hydrogel for Suppression of Oxidative Stress Damage in Cardiomyocytes. Biomaterials 2013, 34, 9071−9081. (703) Hao, T.; Li, J.; Yao, F.; Dong, D.; Wang, Y.; Yang, B.; Wang, C. Injectable Fullerenol/Alginate Hydrogel for Suppression of Oxidative Stress Damage in Brown Adipose-Derived Stem Cells and Cardiac Repair. ACS Nano 2017, 11, 5474−5488. (704) Cleary, J. L.; Condren, A. R.; Zink, K. E.; Sanchez, L. M. Calling All Hosts: Bacterial Communication in Situ. Chem. 2017, 2, 334−358. (705) Routy, B.; Gopalakrishnan, V.; Daillere, R.; Zitvogel, L.; Wargo, J. A.; Kroemer, G. The Gut Microbiota Influences Anticancer Immunosurveillance and General Health. Nat. Rev. Clin. Oncol. 2018, 15, 382−396. (706) Roy, S.; Trinchieri, G. Microbiota: A Key Orchestrator of Cancer Therapy. Nat. Rev. Cancer 2017, 17, 271−285. (707) Garland, M.; Loscher, S.; Bogyo, M. Chemical Strategies to Target Bacterial Virulence. Chem. Rev. 2017, 117, 4422−4461. (708) Hu, B.; Owh, C.; Chee, P. L.; Leow, W. R.; Liu, X.; Wu, Y. L.; Guo, P.; Loh, X. J.; Chen, X. Supramolecular Hydrogels for Antimicrobial Therapy. Chem. Soc. Rev. 2018, 47, 6917−6929. (709) Furuya, E. Y.; Lowy, F. D. Antimicrobial-Resistant Bacteria in the Community Setting. Nat. Rev. Microbiol. 2006, 4, 36−45. (710) Dik, D. A.; Fisher, J. F.; Mobashery, S. Cell-Wall Recycling of the Gram-Negative Bacteria and the Nexus to Antibiotic Resistance. Chem. Rev. 2018, 118, 5952−5984. (711) Tacconelli, E.; Al-Abri, S. S.; Jalil, N. A.; Benzonana, N.; Bhattacharya, S.; Brink, A. J.; Burkert, F. R.; Cars, O.; Cornaglia, G.; Dyar, O. J.; Aboderin, A. O. Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18, 318−327. (712) Natalio, F.; Andre, R.; Hartog, A. F.; Stoll, B.; Jochum, K. P.; Wever, R.; Tremel, W. Vanadium Pentoxide Nanoparticles Mimic Vanadium Haloperoxidases and Thwart Biofilm Formation. Nat. Nanotechnol. 2012, 7, 530−535. (713) Ziegelhoffer, E. C.; Donohue, T. J. Bacterial Responses to Photo-Oxidative Stress. Nat. Rev. Microbiol. 2009, 7, 856−863. (714) Gao, L.; Koo, H. Do Catalytic Nanoparticles Offer an Improved Therapeutic Strategy to Combat Dental Biofilms? Nanomedicine 2017, 12, 275−279. (715) Durmus, N. G.; Taylor, E. N.; Kummer, K. M.; Webster, T. J. Enhanced Efficacy of Superparamagnetic Iron Oxide Nanoparticles against Antibiotic-Resistant Biofilms in the Presence of Metabolites. Adv. Mater. 2013, 25, 5706−5713. (716) Gao, L.; Liu, Y.; Kim, D.; Li, Y.; Hwang, G.; Naha, P. C.; Cormode, D. P.; Koo, H. Nanocatalysts Promote Streptococcus CX


Chemical Reviews

Review

Mutans Biofilm Matrix Degradation and Enhance Bacterial Killing to Suppress Dental Caries in Vivo. Biomaterials 2016, 101, 272−284. (717) Xu, Z.; Qiu, Z.; Liu, Q.; Huang, Y.; Li, D.; Shen, X.; Fan, K.; Xi, J.; Gu, Y.; Tang, Y.; et al. Converting Organosulfur Compounds to Inorganic Polysulfides against Resistant Bacterial Infections. Nat. Commun. 2018, 9, 3713. (718) Sun, H.; Gao, N.; Dong, K.; Ren, J.; Qu, X. Graphene Quantum Dots-Band-Aids Used for Wound Disinfection. ACS Nano 2014, 8, 6202−6210. (719) Liu, S.; Zeng, T. H.; Hofmann, M.; Burcombe, E.; Wei, J.; Jiang, R.; Kong, J.; Chen, Y. Antibacterial Activity of Graphite, Graphite Oxide, Graphene Oxide, and Reduced Graphene Oxide: Membrane and Oxidative Stress. ACS Nano 2011, 5, 6971−6980. (720) Yang, X.; Li, J.; Liang, T.; Ma, C.; Zhang, Y.; Chen, H.; Hanagata, N.; Su, H.; Xu, M. Antibacterial Activity of TwoDimensional MoS2 Sheets. Nanoscale 2014, 6, 10126−10133. (721) Yin, W.; Yu, J.; Lv, F.; Yan, L.; Zheng, L. R.; Gu, Z.; Zhao, Y. Functionalized Nano-MoS2 with Peroxidase Catalytic and nearInfrared Photothermal Activities for Safe and Synergetic Wound Antibacterial Applications. ACS Nano 2016, 10, 11000−11011. (722) Wang, Z.; Dong, K.; Liu, Z.; Zhang, Y.; Chen, Z.; Sun, H.; Ren, J.; Qu, X. Activation of Biologically Relevant Levels of Reactive Oxygen Species by Au/g-C3N4 Hybrid Nanozyme for Bacteria Killing and Wound Disinfection. Biomaterials 2017, 113, 145−157. (723) Fang, G.; Li, W.; Shen, X.; Perez-Aguilar, J. M.; Chong, Y.; Gao, X.; Chai, Z.; Chen, C.; Ge, C.; Zhou, R. Differential PdNanocrystal Facets Demonstrate Distinct Antibacterial Activity against Gram-Positive and Gram-Negative Bacteria. Nat. Commun. 2018, 9, 129. (724) Lin, T.; Zhong, L.; Guo, L.; Fu, F.; Chen, G. Seeing Diabetes: Visual Detection of Glucose Based on the Intrinsic Peroxidase-Like Activity of MoS2 Nanosheets. Nanoscale 2014, 6, 11856−11862. (725) Courtney, C. M.; Goodman, S. M.; McDaniel, J. A.; Madinger, N. E.; Chatterjee, A.; Nagpal, P. Photoexcited Quantum Dots for Killing Multidrug-Resistant Bacteria. Nat. Mater. 2016, 15, 529−534. (726) Courtney, C. M.; Goodman, S. M.; Nagy, T. A.; Levy, M.; Bhusal, P.; Madinger, N. E.; Detweiler, C. S.; Nagpal, P.; Chatterjee, A. Potentiating Antibiotics in Drug-Resistant Clinical Isolates Via StimuliActivated Superoxide Generation. Sci. Adv. 2017, 3, e1701776. (727) Wang, Q. H.; Kalantar-Zadeh, K.; Kis, A.; Coleman, J. N.; Strano, M. S. Electronics and Optoelectronics of Two-Dimensional Transition Metal Dichalcogenides. Nat. Nanotechnol. 2012, 7, 699− 712. (728) Chhowalla, M.; Shin, H. S.; Eda, G.; Li, L. J.; Loh, K. P.; Zhang, H. The Chemistry of Two-Dimensional Layered Transition Metal Dichalcogenide Nanosheets. Nat. Chem. 2013, 5, 263−275. (729) Huang, X.; Zeng, Z.; Zhang, H. Metal Dichalcogenide Nanosheets: Preparation, Properties and Applications. Chem. Soc. Rev. 2013, 42, 1934−1946. (730) Gao, M. R.; Xu, Y. F.; Jiang, J.; Yu, S. H. Nanostructured Metal Chalcogenides: Synthesis, Modification, and Applications in Energy Conversion and Storage Devices. Chem. Soc. Rev. 2013, 42, 2986− 3017. (731) Li, H.; Wu, J.; Yin, Z.; Zhang, H. Preparation and Applications of Mechanically Exfoliated Single-Layer and Multilayer MoS2 and WSe2 Nanosheets. Acc. Chem. Res. 2014, 47, 1067−1075. (732) Jariwala, D.; Sangwan, V. K.; Lauhon, L. J.; Marks, T. J.; Hersam, M. C. Emerging Device Applications for Semiconducting Two-Dimensional Transition Metal Dichalcogenides. ACS Nano 2014, 8, 1102−1120. (733) Lopez-Sanchez, O.; Lembke, D.; Kayci, M.; Radenovic, A.; Kis, A. Ultrasensitive Photodetectors Based on Monolayer MoS2. Nat. Nanotechnol. 2013, 8, 497−501. (734) Kalantar-zadeh, K.; Ou, J. Z.; Daeneke, T.; Strano, M. S.; Pumera, M.; Gras, S. L. Two-Dimensional Transition Metal Dichalcogenides in Biosystems. Adv. Funct. Mater. 2015, 25, 5086− 5099.

(735) Gong, L. J.; Yan, L.; Zhou, R. Y.; Xie, J. N.; Wu, W.; Gu, Z. J. Two-Dimensional Transition Metal Dichalcogenide Nanomaterials for Combination Cancer Therapy. J. Mater. Chem. B 2017, 5, 1873−1895. (736) Mak, K. F.; Lee, C.; Hone, J.; Shan, J.; Heinz, T. F. Atomically Thin MoS2: A New Direct-Gap Semiconductor. Phys. Rev. Lett. 2010, 105, 136805. (737) Liu, C.; Kong, D.; Hsu, P. C.; Yuan, H.; Lee, H. W.; Liu, Y.; Wang, H.; Wang, S.; Yan, K.; Lin, D.; et al. Rapid Water Disinfection Using Vertically Aligned MoS2 Nanofilms and Visible Light. Nat. Nanotechnol. 2016, 11, 1098−1104. (738) He, W.; Kim, H. K.; Wamer, W. G.; Melka, D.; Callahan, J. H.; Yin, J. J. Photogenerated Charge Carriers and Reactive Oxygen Species in ZnO/Au Hybrid Nanostructures with Enhanced Photocatalytic and Antibacterial Activity. J. Am. Chem. Soc. 2014, 136, 750−757. (739) Mao, C.; Xiang, Y.; Liu, X.; Cui, Z.; Yang, X.; Yeung, K. W. K.; Pan, H.; Wang, X.; Chu, P. K.; Wu, S. Photo-Inspired Antibacterial Activity and Wound Healing Acceleration by Hydrogel Embedded with Ag/Ag@AgCl/ZnO Nanostructures. ACS Nano 2017, 11, 9010− 9021. (740) Liu, S.; Yuan, H.; Bai, H.; Zhang, P.; Lv, F.; Liu, L.; Dai, Z.; Bao, J.; Wang, S. Electrochemiluminescence for Electric-Driven Antibacterial Therapeutics. J. Am. Chem. Soc. 2018, 140, 2284−2291. (741) Wang, C.; Fomovsky, M.; Miao, G. X.; Zyablitskaya, M.; Vukelic, S. Femtosecond Laser Crosslinking of the Cornea for NonInvasive Vision Correction. Nat. Photonics 2018, 12, 416−422. (742) Hervera, A.; De Virgiliis, F.; Palmisano, I.; Zhou, L.; Tantardini, E.; Kong, G.; Hutson, T.; Danzi, M. C.; Perry, R. B.; Santos, C. X. C.; et al. Reactive Oxygen Species Regulate Axonal Regeneration through the Release of Exosomal NADPH Oxidase 2 Complexes into Injured Axons. Nat. Cell Biol. 2018, 20, 307−319. (743) Dolgin, E. The Myopia Boom. Nature 2015, 519, 276−278. (744) Langer, R.; Vacanti, J. P. Tissue Engineering. Science 1993, 260, 920−926. (745) Li, Y.; Xiao, Y.; Liu, C. The Horizon of Materiobiology: A Perspective on Material-Guided Cell Behaviors and Tissue Engineering. Chem. Rev. 2017, 117, 4376−4421. (746) Khademhosseini, A.; Langer, R. A Decade of Progress in Tissue Engineering. Nat. Protoc. 2016, 11, 1775−1781. (747) Tsoi, K. M.; MacParland, S. A.; Ma, X. Z.; Spetzler, V. N.; Echeverri, J.; Ouyang, B.; Fadel, S. M.; Sykes, E. A.; Goldaracena, N.; Kaths, J. M.; et al. Mechanism of Hard-Nanomaterial Clearance by the Liver. Nat. Mater. 2016, 15, 1212−1221. (748) Hampton, M. B.; Kettle, A. J.; Winterbourn, C. C. Inside the Neutrophil Phagosome: Oxidants, Myeloperoxidase, and Bacterial Killing. Blood 1998, 92, 3007−3017. (749) Bhattacharya, K.; Mukherjee, S. P.; Gallud, A.; Burkert, S. C.; Bistarelli, S.; Bellucci, S.; Bottini, M.; Star, A.; Fadeel, B. Biological Interactions of Carbon-Based Nanomaterials: From Coronation to Degradation. Nanomedicine 2016, 12, 333−351. (750) Allen, B. L.; Kichambare, P. D.; Gou, P.; Vlasova, II; Kapralov, A. A.; Konduru, N.; Kagan, V. E.; Star, A. Biodegradation of SingleWalled Carbon Nanotubes through Enzymatic Catalysis. Nano Lett. 2008, 8, 3899−3903. (751) Allen, B. L.; Kotchey, G. P.; Chen, Y.; Yanamala, N. V.; KleinSeetharaman, J.; Kagan, V. E.; Star, A. Mechanistic Investigations of Horseradish Peroxidase-Catalyzed Degradation of Single-Walled Carbon Nanotubes. J. Am. Chem. Soc. 2009, 131, 17194−17205. (752) Kagan, V. E.; Konduru, N. V.; Feng, W.; Allen, B. L.; Conroy, J.; Volkov, Y.; Vlasova, II; Belikova, N. A.; Yanamala, N.; Kapralov, A.; et al. Carbon Nanotubes Degraded by Neutrophil Myeloperoxidase Induce Less Pulmonary Inflammation. Nat. Nanotechnol. 2010, 5, 354−359. (753) Kurapati, R.; Russier, J.; Squillaci, M. A.; Treossi, E.; MenardMoyon, C.; Del Rio-Castillo, A. E.; Vazquez, E.; Samori, P.; Palermo, V.; Bianco, A. Dispersibility-Dependent Biodegradation of Graphene Oxide by Myeloperoxidase. Small 2015, 11, 3985−3994. (754) Kurapati, R.; Backes, C.; Menard-Moyon, C.; Coleman, J. N.; Bianco, A. White Graphene Undergoes Peroxidase Degradation. Angew. Chem., Int. Ed. 2016, 55, 5506−5511. CY


Chemical Reviews

Review

(755) Lin, H.; Gao, S.; Dai, C.; Chen, Y.; Shi, J. A Two-Dimensional Biodegradable Niobium Carbide (MXene) for Photothermal Tumor Eradication in NIR-I and NIR-II Biowindows. J. Am. Chem. Soc. 2017, 139, 16235−16247. (756) Walia, S.; Balendhran, S.; Ahmed, T.; Singh, M.; El-Badawi, C.; Brennan, M. D.; Weerathunge, P.; Karim, M. N.; Rahman, F.; Rassell, A.; et al. Ambient Protection of Few-Layer Black Phosphorus Via Sequestration of Reactive Oxygen Species. Adv. Mater. 2017, 29, 1700152. (757) MacNicoll, A.; Kelly, M.; Aksoy, H.; Kramer, E.; Bouwmeester, H.; Chaudhry, Q. A Study of the Uptake and Biodistribution of NanoTitanium Dioxide Using in Vitro and in Vivo Models of Oral Intake. J. Nanopart. Res. 2015, 17, DOI: 10.1007/s11051-015-2862-3. (758) Olmedo, D. G.; Tasat, D. R.; Guglielmotti, M. B.; Cabrini, R. L. Biodistribution of Titanium Dioxide from Biologic Compartments. J. Mater. Sci.: Mater. Med. 2008, 19, 3049−3056. (759) Yao, C. J.; Li, C. C.; Ding, L.; Fang, J.; Yuan, L. L.; Hu, X. F.; Wang, Y. L.; Wu, M. H. Effects of Exposure Routes on the BioDistribution and Toxicity of Titanium Dioxide Nanoparticles in Mice. J. Nanosci. Nanotechnol. 2016, 16, 7110−7117. (760) Fischer, H. C.; Liu, L. C.; Pang, K. S.; Chan, W. C. W. Pharmacokinetics of Nanoscale Quantum Dots: In Vivo Distribution, Sequestration, and Clearance in the Rat. Adv. Funct. Mater. 2006, 16, 1299−1305. (761) Pham, B. T. T.; Colvin, E. K.; Pham, N. T. H.; Kim, B. J.; Fuller, E. S.; Moon, E. A.; Barbey, R.; Yuen, S.; Rickman, B. H.; Bryce, N. S.; et al. Biodistribution and Clearance of Stable Superparamagnetic Maghemite Iron Oxide Nanoparticles in Mice Following Intraperitoneal Administration. Int. J. Mol. Sci. 2018, 19, 205. (762) Gobbo, O. L.; Wetterling, F.; Vaes, P.; Teughels, S.; Markos, F.; Edge, D.; Shortt, C. M.; Crosbie-Staunton, K.; Radomski, M. W.; Volkov, Y.; et al. Biodistribution and Pharmacokinetic Studies of Spion Using Particle Electron Paramagnetic Resonance, MRI and ICP-MS. Nanomedicine 2015, 10, 1751−1760. (763) Hirst, S. M.; Karakoti, A.; Singh, S.; Self, W.; Tyler, R.; Seal, S.; Reilly, C. M. Bio-Distribution and in Vivo Antioxidant Effects of Cerium Oxide Nanoparticles in Mice. Environ. Toxicol. 2013, 28, 107− 118. (764) Elgrabli, D.; Beaudouin, R.; Jbilou, N.; Floriani, M.; Pery, A.; Rogerieux, F.; Lacroix, G. Biodistribution and Clearance of TiO2 Nanoparticles in Rats after Intravenous Injection. PLoS One 2015, 10, e0124490. (765) Abe, S.; Koyama, C.; Uo, M.; Akasaka, T.; Kuboki, Y.; Watari, F. Time-Dependence and Visualization of TiO2 and Pt Particle Biodistribution in Mice. J. Nanosci. Nanotechnol. 2009, 9, 4988−4991. (766) Lartigue, L.; Alloyeau, D.; Kolosnjaj-Tabi, J.; Javed, Y.; Guardia, P.; Riedinger, A.; Pechoux, C.; Pellegrino, T.; Wilhelm, C.; Gazeau, F. Biodegradation of Iron Oxide Nanocubes: High-Resolution in Situ Monitoring. ACS Nano 2013, 7, 3939−3952. (767) Arami, H.; Khandhar, A.; Liggitt, D.; Krishnan, K. M. In Vivo Delivery, Pharmacokinetics, Biodistribution and Toxicity of Iron Oxide Nanoparticles. Chem. Soc. Rev. 2015, 44, 8576−8607. (768) Saito, M.; Matsuura, T.; Nagatsuma, K.; Tanaka, K.; Maehashi, H.; Shimizu, K.; Hataba, Y.; Kato, F.; Kashimori, I.; Tajiri, H.; et al. The Functional Interrelationship between Gap Junctions and Fenestrae in Endothelial Cells of the Liver Organoid. J. Membr. Biol. 2007, 217, 115−121. (769) Graham, U. M.; Tseng, M. T.; Jasinski, J. B.; Yokel, R. A.; Unrine, J. M.; Davis, B. H.; Dozier, A. K.; Hardas, S. S.; Sultana, R.; Grulke, E. A.; et al. Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free-Radical Scavenging Activity and Oxidative Stress. ChemPlusChem 2014, 79, 1083−1088. (770) Xia, T.; Kovochich, M.; Brant, J.; Hotze, M.; Sempf, J.; Oberley, T.; Sioutas, C.; Yeh, J. I.; Wiesner, M. R.; Nel, A. E. Comparison of the Abilities of Ambient and Manufactured Nanoparticles to Induce Cellular Toxicity According to an Oxidative Stress Paradigm. Nano Lett. 2006, 6, 1794−1807.

(771) Sharifi, S.; Behzadi, S.; Laurent, S.; Forrest, M. L.; Stroeve, P.; Mahmoudi, M. Toxicity of Nanomaterials. Chem. Soc. Rev. 2012, 41, 2323−2343. (772) Peynshaert, K.; Manshian, B. B.; Joris, F.; Braeckmans, K.; De Smedt, S. C.; Demeester, J.; Soenen, S. J. Exploiting Intrinsic Nanoparticle Toxicity: The Pros and Cons of Nanoparticle-Induced Autophagy in Biomedical Research. Chem. Rev. 2014, 114, 7581−7609. (773) Zhao, Y.; Howe, J. L.; Yu, Z.; Leong, D. T.; Chu, J. J.; Loo, J. S.; Ng, K. W. Exposure to Titanium Dioxide Nanoparticles Induces Autophagy in Primary Human Keratinocytes. Small 2013, 9, 387−392. (774) Joshi, A.; Punyani, S.; Bale, S. S.; Yang, H.; Borca-Tasciuc, T.; Kane, R. S. Nanotube-Assisted Protein Deactivation. Nat. Nanotechnol. 2008, 3, 41−45. (775) Klaine, S. J.; Alvarez, P. J.; Batley, G. E.; Fernandes, T. F.; Handy, R. D.; Lyon, D. Y.; Mahendra, S.; McLaughlin, M. J.; Lead, J. R. Nanomaterials in the Environment: Behavior, Fate, Bioavailability, and Effects. Environ. Toxicol. Chem. 2008, 27, 1825−1851. (776) Landsiedel, R.; Ma-Hock, L.; Kroll, A.; Hahn, D.; Schnekenburger, J.; Wiench, K.; Wohlleben, W. Testing Metal-Oxide Nanomaterials for Human Safety. Adv. Mater. 2010, 22, 2601−2627. (777) Sharma, V. K.; Filip, J.; Zboril, R.; Varma, R. S. Natural Inorganic Nanoparticles–Formation, Fate, and Toxicity in the Environment. Chem. Soc. Rev. 2015, 44, 8410−8423. (778) Stone, V.; Donaldson, K. Nanotoxicology: Signs of Stress. Nat. Nanotechnol. 2006, 1, 23−24. (779) Fadeel, B.; Farcal, L.; Hardy, B.; Vazquez-Campos, S.; Hristozov, D.; Marcomini, A.; Lynch, I.; Valsami-Jones, E.; Alenius, H.; Savolainen, K. Advanced Tools for the Safety Assessment of Nanomaterials. Nat. Nanotechnol. 2018, 13, 537−543. (780) Bourquin, J.; Milosevic, A.; Hauser, D.; Lehner, R.; Blank, F.; Petri-Fink, A.; Rothen-Rutishauser, B. Biodistribution, Clearance, and Long-Term Fate of Clinically Relevant Nanomaterials. Adv. Mater. 2018, 30, 1704307. (781) Grimme, S.; Schreiner, P. R. Computational Chemistry: The Fate of Current Methods and Future Challenges. Angew. Chem., Int. Ed. 2018, 57, 4170−4176. (782) Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.; DiRocco, D. A.; Streckfuss, E. C.; Campeau, L. C.; Cernak, T.; Vachal, P.; Davies, I. W.; et al. Chemistry Informer Libraries: A Chemoinformatics Enabled Approach to Evaluate and Advance Synthetic Methods. Chem. Sci. 2016, 7, 2604−2613. (783) Dugger, S. A.; Platt, A.; Goldstein, D. B. Drug Development in the Era of Precision Medicine. Nat. Rev. Drug Discovery 2017, 17, 183− 196. (784) Wang, Y.; Sun, S.; Zhang, Z.; Shi, D. Nanomaterials for Cancer Precision Medicine. Adv. Mater. 2018, 30, 1705660. (785) von Roemeling, C.; Jiang, W.; Chan, C. K.; Weissman, I. L.; Kim, B. Y. S. Breaking Down the Barriers to Precision Cancer Nanomedicine. Trends Biotechnol. 2017, 35, 159−171. (786) Wang, A. Q.; Li, J.; Zhang, T. Heterogeneous Single-Atom Catalysis. Nat. Rev. Chem. 2018, 2, 65−81. (787) Liu, L.; Corma, A. Metal Catalysts for Heterogeneous Catalysis: From Single Atoms to Nanoclusters and Nanoparticles. Chem. Rev. 2018, 118, 4981−5079. (788) Yang, X. F.; Wang, A.; Qiao, B.; Li, J.; Liu, J.; Zhang, T. SingleAtom Catalysts: A New Frontier in Heterogeneous Catalysis. Acc. Chem. Res. 2013, 46, 1740−1748. (789) Zhang, H. B.; Liu, G. G.; Shi, L.; Ye, J. H. Single-Atom Catalysts: Emerging Multifunctional Materials in Heterogeneous Catalysis. Adv. Energy Mater. 2018, 8, 1701343. (790) Thomas, J. M. The Concept, Reality and Utility of Single-Site Heterogeneous Catalysts (SSHCs). Phys. Chem. Chem. Phys. 2014, 16, 7647−7661. (791) Cui, X. J.; Li, W.; Ryabchuk, P.; Junge, K.; Beller, M. Bridging Homogeneous and Heterogeneous Catalysis by Heterogeneous SingleMetal-Site Catalysts. Nat. Catal. 2018, 1, 385−397. (792) Shi, J. L. Single-Atom Co-Doped MoS2 Monolayers for Highly Active Biomass Hydrodeoxygenation. Chem. 2017, 2, 468−469. CZ


Chemical Reviews

Review

(793) Wei, S.; Li, A.; Liu, J. C.; Li, Z.; Chen, W.; Gong, Y.; Zhang, Q.; Cheong, W. C.; Wang, Y.; Zheng, L.; et al. Direct Observation of Noble Metal Nanoparticles Transforming to Thermally Stable Single Atoms. Nat. Nanotechnol. 2018, 13, 856−861. (794) Deng, D.; Chen, X.; Yu, L.; Wu, X.; Liu, Q.; Liu, Y.; Yang, H.; Tian, H.; Hu, Y.; Du, P.; et al. A Single Iron Site Confined in a Graphene Matrix for the Catalytic Oxidation of Benzene at Room Temperature. Sci. Adv. 2015, 1, e1500462. (795) Agrahari, V.; Agrahari, V. Facilitating the Translation of Nanomedicines to a Clinical Product: Challenges and Opportunities. Drug Discovery Today 2018, 23, 974−991. (796) Hassan, S.; Prakash, G.; Ozturk, A.; Saghazadeh, S.; Sohail, M. F.; Seo, J.; Dockmeci, M.; Zhang, Y. S.; Khademhosseini, A. Evolution and Clinical Translation of Drug Delivery Nanomaterials. Nano Today 2017, 15, 91−106. (797) Hare, J. I.; Lammers, T.; Ashford, M. B.; Puri, S.; Storm, G.; Barry, S. T. Challenges and Strategies in Anti-Cancer Nanomedicine Development: An Industry Perspective. Adv. Drug Delivery Rev. 2017, 108, 25−38. (798) Min, Y.; Caster, J. M.; Eblan, M. J.; Wang, A. Z. Clinical Translation of Nanomedicine. Chem. Rev. 2015, 115, 11147−11190. (799) Shi, J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer Nanomedicine: Progress, Challenges and Opportunities. Nat. Rev. Cancer 2017, 17, 20−37. (800) Balasubramanian, V.; Liu, Z.; Hirvonen, J.; Santos, H. A. Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines. Adv. Healthcare Mater. 2018, 7, 1700432.

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