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Aggregation-Induced Emission: A Trailblazing Journey to the Field of Biomedicine Chunlei Zhu,†,‡ Ryan T. K. Kwok,† Jacky W. Y. Lam,† and Ben Zhong Tang*,†,§,∥

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Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Institute for Advanced Study, Department of Chemical and Biological Engineering and Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China ‡ Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China § Centre for Aggregation-Induced Emission, SCUT-HKUST Joint Research Institute, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China ∥ HKUST-Shenzhen Research Institute, No. 9 Yuexing First RD, South Area, Hi-Tech Park, Nanshan, Shenzhen 518057, China S Supporting Information *

ABSTRACT: The emergence of the aggregation-induced emission (AIE) concept significantly changes the cognition of the scientific community toward classic photophysical phenomena. More importantly, the AIE phenomenon has brought huge opportunities for the analysis of bioactive species, the monitoring of complicated biological processes, and the elucidation of key physiological and pathological behaviors. As a class of promising luminescent materials, AIE luminogens (AIEgens) are weakly or non-emissive in the form of isolated molecular species but emit particularly strong fluorescence in the aggregated and solid states. Motivated by the prominent advantages such as high brightness, large Stokes shift, excellent photostability, and good biocompatibility, AIEgen-based bioprobes have been widely explored in the field of biomedicine. This review aims to provide a systematic summary of the developmental history and an in-depth perspective of the current landscape of AIE in the biomedical field, with an emphasis on the discussions of major working principles. The milestones of the historical development of AIE in the biomedical field are first reviewed. A total of four major research directions are then extracted, including biomacromolecule sensing (at the molecular level), in vitro cell imaging (at the cellular level), in vivo imaging (at the animal level), and cancer theranostics (at the cellular and animal levels), together with clear-cut tables showing comprehensive cases for further study. Lastly, this review is concluded by the discussions of several perspectives on future directions. It is believed that AIEgen-based bioprobes will play vital roles in the exploration of mysterious life processes by integration with various cutting-edge modalities and techniques with an ultimate goal of addressing more healthcare issues. KEYWORDS: aggregation-induced emission, biosensing, cell imaging, in vivo bioimaging, theranostics, biomedical applications

1. INTRODUCTION In the late 20th century, a large number of significant discoveries and tremendous advancements have been made in life sciences, particularly in the field of molecular biology, which remarkably initiate the enthusiasm of scientists toward unraveling various mysteries hidden within living creatures.1 Stepping into the 21st century, life sciences have ever been developing at a breathtaking pace, exemplified by the discovery of naturally occurring biological events. For instance, a recent study suggests that it is two microtubule spindles, rather than one as in traditional thought, that independently modulate the behaviors of maternal and paternal chromosomes for the first embryonic division.2 To reveal the underlying operating rules and maximize our understanding on various biological systems, it is critical to harnessing diverse luminescence techniques to shed light on the unknown “black box” that precisely regulates © XXXX American Chemical Society

highly ordered life processes. Despite a myriad of imaging modalities have been established, fluorescence imaging (FL imaging) is regarded as an indispensable technique for biomedical studies due to its high sensitivity, excellent spatiotemporal resolution, noninvasive attribute, rapid and real-time responsiveness, and facile accessibility.3 In view of these prominent advantages, fluorescence-enabling techniques play an irreplaceable role for the analysis of bioactive species, monitoring of complicated biological processes, and elucidation of key physiological and pathological phenomena.2,4−6 The enormous advancements of various imaging techniques significantly rely on the use of exogenous contrast agents to Received: October 9, 2018 Accepted: October 30, 2018 Published: October 30, 2018 A

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Figure 1. Schematic illustration showing the mechanisms of the AIE phenomenon.

first time, coined the concept of aggregation-induced emission (AIE).32 Interestingly, Stokes also observed a similar phenomenon when he studied another type of materials (i.e., platinocyanides), which can be traced back to the year of 1853.33 Such an intriguing discovery breaks traditional cognitive constrains and motivates us to mechanistically elucidate this “unusual” phenomenon. In short, AIE luminogens (AIEgens) are a class of materials that are weakly emissive or non-emissive in dilute solutions (i.e., isolated molecular species) but emit particularly strong fluorescence in the aggregated and solid states. So far, the restriction of intramolecular motions (RIM), including both the restriction of intramolecular rotations (RIR) and the restriction of intramolecular vibrations (RIV), is regarded as the primary mechanism to interpret the AIE phenomenon (Figure 1).29,30 When AIEgens are uniformly dissolved in solutions, the active intramolecular rotations (e.g., propeller-like tetraphenylethene, TPE) and vibrations (e.g., shell-like 10,10′,11,11′-tetrahydro5,5′-bidibenzo[a,d][7]-annulenylidene, THBA) dramatically consume the excitation energy to facilitate non-radiative decay. Upon aggregation, the intramolecular motions of these AIEgens are significantly restrained, which efficiently converts the consumption pathways from non-radiative relaxation to radiative decay. In addition, the detrimental π−π stacking in ACQ luminogens is also hindered in AIEgens because of the nonplanar molecular conformations. With the emergence of mounting evidence, the RIM mechanism has been verified to be a tenable argument to account for the AIE phenomenon, promoting the successful design and development of a myriad of AIEgens with diverse molecular structures and physicochemical properties.34−38 In contrast to traditional organic dyes, AIEgens typically exhibit high fluorescence quantum yields and extraordinary photostability in the aggregated and solid states, which are particularly preferred for high-quality FL imaging and long-term fluorescence tracking. Currently, the emission wavelength of various reported AIEgens already covers the entire visible spectrum and is extending to the near-infrared (NIR) range.30,39−43 Meanwhile, natural luminogens with the AIE properties are also identified to enrich the molecular library of AIEgens.44,45 As reflected by the rapidly growing publications of AIE in the

facilitate high-quality imaging. At present, numerous fluorescent bioprobes have been designed and developed for FL imaging, most of which have already elicited remarkable impacts on the research paradigm of biological studies. These fluorescent materials include but are not limited to organic dyes,7−9 fluorescent conjugated polymers,10−13 quantum dots,14,15 rare-earth ion-based nanoparticles (e.g., lanthanidedoped up-conversion nanoparticles),16−18 metal nanoclusters,19−21 carbon nanomaterials (e.g., carbon nanotubes22,23 and carbon nanodots),24,25 and various fluorescent proteins.26,27 Among them, organic materials possess a series of outstanding properties, such as good biocompatibility, tunable spectral characteristics, facile processability, and versatile modification strategies, rendering them fantastic candidates for FL imaging. In particular, when most traditional organic dyes are used at high concentrations or in the aggregated state, the intrinsic fluorescence signals are strikingly diminished or even vanish as a result of intermolecular π−π stacking, which is well-known as the aggregation-caused quenching (ACQ) effect.28−31 Because most classic organic dyes are characterized by multiple aromatic rings and/or long conjugated chains, the structural hydrophobicity makes them prone to forming irregular aggregates in aqueous environments, leading to severe selfquenching. To minimize the ACQ effect, dilute solutions of organic dyes are used as alternatives for various imaging applications. In this scenario, however, the decreased number of fluorescent molecules are more vulnerable to external highenergy incident light, resulting in undesirable photobleaching. In addition, the ACQ phenomenon also takes effect when the organic dyes are doped or encapsulated into other loading matrix. Therefore, the overall brightness of an individual nanoparticle cannot be proportionally enhanced by simply increasing the loading efficiency. All of these drawbacks greatly impede the performances of organic dyes for biological applications. It is thus critically essential to develop a new class of prototype materials to address these issues so as to revolutionize FL imaging. In 2001, our group reported that a type of unique luminogens (i.e., silole derivatives) exhibited significantly enhanced fluorescence in the aggregated state, and, for the B

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Figure 2. Milestones of the historical development of AIE in the biomedical field.

past decade, the use of AIEgens for biomedical applications represents a new research frontier, which brings in new vigor and vitality for the exploration of various sophisticated biological systems. This review aims to provide a systematic summary of the developmental history and an in-depth perspective on the current landscape of AIE in the biomedical field, with an emphasis on the discussions of major working principles rather than a detailed introduction of specific cases. We first review the milestones of the historical development of AIE in the biomedical field to give an overall idea of what roadmap AIE has followed to reshape this research field. We further categorize current research topics into four major directions, including biomacromolecule sensing (at the molecular level), in vitro cell imaging (at the cellular level), in vivo imaging (at the animal level), and cancer theranostics (at the cellular and

animal levels). In these individual sections, we summarize the general working principles and design strategies, together with clear-cut tables showing comprehensive cases for further study. Lastly, we conclude this review by offering some perspectives on future directions.

2. OVERVIEW OF THE TRAILBLAZING JOURNEY OF AIE TO THE FIELD OF BIOMEDICINE The introduction of the AIE concept into the scientific community has attracted tremendous research interests and inspired a wide spectrum of applications, including chemical sensing, optoelectronic devices, and biomedical applications, among others.30,46−48 In particular, the development of AIE in the field of biomedicine has exhibited an inexhaustible motive force, holding great potential to resolve various healthcare issues in human beings.31,39−41,49−62 To clearly present the key C

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Figure 3. Schematic illustration showing the working principles of AIEgen-based “turn-on” systems: (A) electrostatic assembly, (B) solubility change, (C) specific recognition, (D) hydrophobic interaction, and (E) PET or ET disruption.

the early stage, highly dispersed AIEgens and AIE-active luminogens are employed to sense and interact with a set of biological species, including ions,67−69 small molecules,70−73 and functional biomacromolecules (e.g., DNA,74−76 proteins,76−80 and polysaccharides).81,82 Later on, the possibility of using AIEgens for cell imaging is also demonstrated. Despite early studies are basically limited to non-specific cell imaging with the assistance of highly dispersed AIEgens, AIE-active luminogens, and their aggregates,83−86 AIEgens bearing particularly designed moieties (e.g., ionic salts and peptides) are subsequently synthesized to identify various intracellular organelles53 and biogenic species (e.g., small molecules and enzymes) that typically reflect intracellular environment (e.g., pH, viscosity, and health conditions) and cellular status (e.g., apoptosis, autophagy, and metastasis).31,87,88 Aside from conventional FL imaging, photoactivatable AIEgens are also developed to enable super-resolution FL imaging.89 Inspired by the enormous benefits of “all-in-one” nanomaterials, a number of AIEgen-based bioprobes are developed, which are not only used for in vitro cell imaging (e.g., cancer cell targeting and discrimination of bacteria) but also leveraged to animal levels for in vivo applications (e.g., tumor labeling and vascular imaging).31,90−95 To provide large tissue-penetration depth, the emission spectra of AIE probes are pushing

historical nodes, we deliberately combed the timeline of major developments of AIE in the biomedical field over the past 18 years, the results of which are shown in Figure 2. Similar to any other research directions, the progress of AIE in the biomedical field abides by a similar rule. Overall, the fundamental investigations have experienced a slow-to-fast process. Since the concept of AIE was proposed in 2001, there is a relative stagnation period in the first five years. During this stage, the research is primarily focused on the mechanistic understanding of the AIE phenomenon and exploration of all possibilities of AIEgens.28,63−65 The first biomedical application of AIE was reported in 2004, in which the investigators skillfully utilized silole-based AIEgens to significantly increase the sensitivity of immunoassays.66 Afterward, the prominent properties of AIEgens have attracted intense attention, which opens up the door of validating the practicality of AIEgens in various biological systems.31,39−41,49−62 Taking “aggregation-induced emission OR AIE” and “bio*” as the keywords together with the year confined to “2008−2018” in the Web of Science, more than 1900 publications have been retrieved (as of August 1, 2018), indicating the rapid propagation of AIE in the biomedical field during the past 10 years. Specifically, the research objects are shifting from simple molecular systems to complicated cell and animal models. In D

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groups110,111 and peptides)88,112−114 (Figure 3B). When enzymes selectively remove these hydrophilic groups, the solubility of AIEgens is significantly decreased, leading to the formation of highly fluorescent aggregates that are composed of hydrophobic cores. To ensure high selectivity and reliability, this type of working principle typically requires a specially designed hydrophilic moiety to respond to a specific enzyme. (iii) Specific recognition. The third design principle is based on the specific recognition of analytes (e.g., integrin and DNA chains) using AIEgens with targeting ligands (e.g., RGD peptide115 and complementary DNA chains)116−119 (Figure 3C). Similarly, the high affinity between the two species blocks the intramolecular motions of AIEgens (for ligand−receptor binding) or facilitates molecular aggregation (for DNA hybridization), resulting in the turn-on fluorescence response. (iv) Hydrophobic interaction. The fourth design principle is related to the hydrophobic interactions between amphiphilic AIEgens and hydrophobic domains in the folding structures of proteins (Figure 3D).74,77,120,121 The docked AIEgens are prone to the formation of aggregates due to the limited space in the hydrophobic pocket of proteins, which activates the RIM process to light up the AIEgens. The feedback fluorescence signals are very useful to monitor the folding processes or conformational transitions of proteins in a realtime fashion.122,123 (v) PET or ET disruption. The fifth design principle involves the disruption of processes of non-radiative decay, such as photoinduced electron transfer (PET) and energy transfer (ET) (Figure 3E). This type of AIEgens needs to be modified with quencher groups (e.g., maleimide)124 or mixed with quenching species (e.g., dabcyl groups125 and methyl parathion).126 In the very beginning, the AIEgens are nonemissive as a result of either electron or energy transfer from the AIEgens to the quencher groups, ensuring low background signals. Once the analytes react with the quenchers to inactivate its quenching capability or cleave the quencher groups to make them far away from the AIEgens, the consumption pathway of the excited-state energy is remarkably shut down, giving rise to fluorescence recovery. It is worth noting that such a strategy is particularly applicable to AIEgens initially in the aggregated state (e.g., encapsulated in silica nanoparticles), making it feasible to serve as turn-on solid-state biosensors. In certain situations, the excited-state intramolecular proton transfer (ESIPT) is also combined with the AIE mechanism to concurrently trigger the RIM process.127−129 Because the ESIPT process is highly dependent on the intramolecular hydrogen bonding, it is feasible to achieve the light-up sensing of biomacromolecules by controlling the “on” and “off” states of hydrogen bond. Taking advantages of these major design principles as well as their derivatives, a myriad of biomacromolecules have been successfully analyzed with high sensitivity and fidelity. In view of the limited space, detailed discussions of representative examples for each design principle are not included in this review. To maintain the integrity of this article and make it serve as a search tool, we prepare a comprehensive table detailing the specific cases of biomacromolecules that have been investigated using the aforementioned design principles (Table S1). For those who are interested, it is recommended to refer to the corresponding references for further study.

bathochromically from far red, NIR-I (700−900 nm) to NIR-II (1000−1700 nm).42,94,96,97 Meanwhile, multiphoton imaging (e.g., two-photon and three-photon)31,98 and photoacoustic imaging (PA imaging)37 are recently developed as alternatives to retrieve feedback signals from deep tissues. In addition to the development of bioimaging techniques for diagnostic purposes, a series of advanced AIEgen-based systems has successively sprung up for disease theranostics, including image-guided chemotherapy,99 image-guided photodynamic therapy (PDT),100,101 image-guided gene delivery,102 and photothermal therapy (PTT)37 as well as the integration of two or more of the aforementioned modes (termed as combination therapy).103 More recently, AIEgen-based smart systems that are able to reversibly switch between two distinct molecular states for both high-quality imaging and effective therapy represent a new research direction, providing an ideal solution for the improved treatment of diseases.104

3. BRINGING AIEGENS INTO BIOMACROMOLECULE SENSING Biomacromolecules are biomolecules that are featured as high molecular weights and complex molecular structures. Typically, these biological macromolecules are built from a set of simple monomeric units that are covalently linked with each other to form large polymers. Representative examples of biomacromolecules include nucleic acids (i.e., DNA and RNA), proteins, carbohydrates, and lipids, which make up the majority of dry mass of cells.105 Considering the significant biological functions of biomacromolecules, it is of great importance to establish robust approaches for accurate, sensitive, and quantitative detection of these biogenic species. AIEgens are intrinsically a class of light-up probes that can afford low signal-to-noise ratio and high sensitivity to identify a minute quantity of target analytes in a biological system. Meanwhile, different from traditional fluorescent probes, AIEgens are able to perform at high concentrations without being affected by the detrimental ACQ effect. To make AIEgens compatible to biological systems, these probes are typically tethered with water-soluble groups and thus weakly emissive in aqueous solutions. Upon selective interaction with target analytes, the turn-on fluorescence could be effectively initiated due to the formation of aggregates with restricted intramolecular motions. In addition to these superior properties, AIEgens are also capable of offering excellent photostability and large Stokes shift, rendering them ideal candidates for precise and reliable sensing of biomacromolecules. Looking back to the reported systems for biomacromolecule sensing, five major design principles have been established for fluorescence light-up analysis, which are summarized in Figure 3. (i) Electrostatic assembly. The first design principle is based on electrostatic assembly, in which charged AIEgens and oppositely charged species (e.g., DNA,74−76,106 RNA,107,108 and heparin)81,82,109 are able to form electrostatic complexes via electrostatic interactions (Figure 3A). Under such circumstances, the AIEgens are forced to be in close proximity, resulting in the activation of the RIM process and thus remarkably enhanced fluorescence. It should be pointed out that hydrophobic interactions also contribute to the complexation process, particularly for those molecules with aromatic or hydrophobic structures (e.g., TPE and DNA bases). (ii) Solubility change. The second design principle involves solubility change during catalytic reactions between enzymes and AIEgens conjugated with hydrophilic moieties (e.g., ionic

4. BRINGING AIE INTO IN VITRO CELL IMAGING Fluorescence cell imaging has become an indispensable technique for modern cell biology, allowing for the visualE

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Figure 4. Schematic illustration showing various AIEgen-based bioprobes for bioimaging: (A) water-soluble AIEgen, (B) bare AIEgen dot, (C) AIEgen/biopolymer dot, (D) AIEgen/silica dot, (E) AIEgen/polymer dot, and (F) polymer AIEgen dot.

recognition and solubility change. This strategy is able to reflect the levels of intracellular biogenic species, which is quite useful to reveal the intracellular environments and critical cellular status and processes (e.g., apoptosis88,112,142,145,158 and autophagy).146 (ii) Bare AIEgen dots. If the water solubility of AIEgens is not strong enough to make them molecularly dissolved in biological fluids, loose or tight nanoaggregates (depending on the chemical structures) will be formed once their organic solutions (e.g., water-miscible THF, DMF, and DMSO) are injected into aqueous buffer, which are classified to the second category (Figure 4B). On the one hand, bare AIEgen dots can be directly used for nonspecific imaging probably via stochastic pinocytosis or unknown receptormediated endocytosis.44,85,159,160 On the other hand, this type of bioprobes can directly target specific organelles (e.g., mitochondria, 43,89,93,161−168 lipid droplets, 169−175 lysosomes,129,174,176−178 cytoplasm membrane,179 nucleolus)180 and microrganisms (e.g., bacteria),181 presumably through a process involving extracellular disintegration of nanoaggregates and intracellular rearrangement at specific sites. (iii) AIEgen/ biopolymer dots. In view of the biocompatibility and biodegradability, biopolymers are harnessed as the loading matrix for AIEgens via either covalent grafting (e.g., chitosan,182−184 dextran,185 or starch)186 or noncovalent encapsulation [e.g., bovine serum albumin (BSA)],86,187 which are summarized as the third category (Figure 4C). It should be pointed out that, for noncovalent binding, chemical cross-linkers (e.g., glutaraldehyde) are typically needed to tighten and stabilize the resultant nanoparticles. Because the AIEgen/BSA dots are characterized by net negative charges in aqueous solutions, electrostatic interactions can be used to functionalize the nanoparticles with targeting moieties (e.g., RGD) for receptor-mediated binding and endocytosis.187 (iv) AIEgen/silica dots. Silica nanoparticles are well-known by their biocompatibility, biological inertness, tunable sizes, and facile surface modification.188 As such, the fourth category involves the use of nonfunctionalized and siloxane-functionalized AIEgens to fabricate AIEgen/silica dots via physical encapsulation inside the silica shell83,99,189−191 and chemical

ization of subcellular structures and cellular processes under the microscope.130 As discussed earlier, the technological advancements of FL imaging are strongly dependent on the utilization of versatile fluorescent materials to offer robust signals and reliable information on the behaviors of cells/ microorganisms for clinical analyses and medical intervention, in which AIEgens represent a class of promising candidates. To continue the trailblazing journey of AIE in the biomedical field, the objects of interest are further leveraged from the molecular level (i.e., biomacromolecules) to cellular level (i.e., cells and microorganisms). In addition to high brightness, large Stokes shift, and good photostability, AIEgens are able to provide two additional features for cell imaging, namely, excellent biocompatibility and wash-free characteristic, which are enabled by the formation of less-disruptive organic aggregates and non-luminescence of molecularly dissolved AIEgens, respectively. Under such circumstances, a myriad of new forms of AIEgen-based bioprobes are generated to meet the requirements of diverse intracellular microenvironments. Through systematic literature survey, the reported AIEgenbased bioprobes can be divided into six major categories, as shown in Figure 4. (i) Water-soluble AIEgens. The first type of bioprobes typically refers to AIEgens that are molecularly dissolved in aqueous biological fluids (Figure 4A). To endow the AIEgens with sufficient water-solubility, various hydrophilic moieties are employed to decorate the hydrophobic core, including ionic groups,38,108,127,131−137 peptides,88,112,115,138−149 carbohydrates,128,150−152 DNAs,153 aptamers, 154,155 antibodies, 156 and poly(ethylene glycol) (PEG).157 With the aid of electrostatic assembly and hydrophobic interaction, ionic-type AIEgens (mostly with positive charges) are able to fluorescently label the regions of mammalian cells and microorganisms that possess oppositely charged species and hydrophobic domains (e.g., cell membranes and DNAs). If the AIEgens are equipped with targeting moieties (e.g., RGD for integrin αvβ3)115 and cleavable groups (e.g., phosphate for alkaline phosphatase127 and DEVD peptide for intracellular caspase-3/7),88 the turn-on fluorescence could be initiated via the mechanisms of specific F

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ACS Applied Bio Materials conjugation into the building networks or surfaces,192−194 respectively (Figure 4D). If the surface of silica nanoparticles has redundant amino groups, functional moieties (e.g., biotin,195 folic acid,96,196 and aptamers)197 can be grafted onto the AIEgen/silica dots for receptor-mediated bioimaging. (v) AIEgen/polymer dots. The fifth category refers to noncovalent incorporation of AIEgens into synthetic amphiphilic polymer matrix via simple physical encapsulation (Figure 4E).36,84,90,198 Given the good biocompatibility and biodegradability, minimized nonspecific interactions with biological species, versatile surface functionalization, and long blood circulation, this type of probes is most widely employed for bioimaging both in vitro and in vivo, in which FDA-approved polymers [e.g., 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol) (DSPE-PEG) and Pluronic F127] have attracted intense interests.199 Similarly, the AIEgen/polymer dots can be further conjugated with various targeting moieties (e.g., folic acid,98,200−202 RGD,203 cellpenetrating peptides,204−209 streptavidin,210 antibodies,211 and aptamers)212 to achieve specific biological functions. In particular, coencapsulation of AIEgens and reactive peroxalates into the same nanoparticle provides a new platform to utilize chemiluminescence for the intracellular imaging of hydrogen peroxide.91 (vi) Polymer AIEgen dots. The sixth category involves the introduction of small-molecule AIEgens into the backbone or side-chains of synthetic polymers to yield AIE polymers, which are subjected to molecular assembly to form polymer AIEgen dots (Figure 4F).213−223 Due to the steric hindrance imposed by the backbone and side chains, the intramolecular motions are easily dampened to induce enhanced emission. In view of the tunable structures, compositions, and morphology as well as diverse modifications, this type of probes is also regarded as a useful tool for various biomedical applications. Likewise, we also prepare a comprehensive table summarizing the specific applications of these bioprobes for in vitro cell imaging, including nonspecific cell imaging, receptor-mediated targeting and endocytosis, organelle-specific imaging, cell environment imaging, and cell status and process imaging (Table S2).

affords deeper tissue penetration and less light−tissue interaction and is thus considered as the ideal biological window.227 In addition, chemiluminescence, involving the utilization of peroxalates as the source of chemical energy and luminogens as the emitters, holds great potential to achieve sensitive and high-quality bioimaging as these signals are typically not interfered by background noises (i.e., photoexcitation and autofluorescence from endogenous species).228,229 On the other hand, novel modalities that utilize the intrinsic photophysical properties of AIEgen-based bioprobes are delicately established, such as multiphoton imaging and PA imaging. Multiphoton imaging refers to the use of long-wavelength, low-energy excitation light (typically in the NIR region) to irradiate the biological samples for noninvasive deep-tissue imaging, the process of which involves the simultaneous absorption of two or three photons to be raised to the excited state.230,231 Given that the excitation only occurs at the tiny focal point of a laser beam, the background signal and out-of-focus absorption are significantly eliminated, providing high-resolution images and reduced photobleaching and photodamage to biological specimens.232 In recent years, bioprobes characterized by strong PA effect have attracted intensive interests.233−235 PA imaging is a class of noninvasive imaging modalities for clinical use.236−238 Making use of PA contrast agents that convert the absorbed light energy into ultrasonic waves, it is possible to acquire superior biological images at the depth of several centimeters together with a desired spatial resolution (ca. 100 μm).236,239,240 Motivated by the desired performances of AIEgens in in vitro fluorescence cell imaging, researchers further extended their potential applications for in vivo bioimaging. In comparison to small molecules, nanosized bioprobes offer numerous merits for in vivo applications, such as enriched physicochemical properties, facile surface functionalization, and, most importantly, resistance to rapid blood clearance.241 Despite bare AIEgen dots have been successfully applied to simple animal models (e.g., zebrafish),165,173 it remains challenging to achieve long-time circulation in higher animals (e.g., mouse) because of the complicated interactions with various blood components. To prolong blood circulation, the introduction of PEG chains is verified to be an effective strategy, which typically serve as a hydrophilic sheath to camouflage exogenous nanoparticles and prevent them from rapid clearance by the reticuloendothelial system.241 In this regard, biocompatible polymer/AIEgen dots are most widely harnessed for in vivo bioimaging.62 In addition, AIEgen-based bioprobes with far-red/NIR emissions34,36,42,86,94,96,97,187,204,207,242−244 and chemiluminescence91,101,245 as well as multiphoton35,98,209,246−254 and PA imaging37,54,97,104 modalities have been introduced in this research field. Among various applications of in vivo bioimaging, tumortargeted imaging and vascular imaging represents two major directions to be studied. As of today, cancer is still one of the leading causes of death across the globe.255 The noninvasive characterization of cancer not only sheds light on the pathological state of neoplastic tissues but also provides a strategy to monitor the therapeutic index of a given anticancer agent. In general, the fast-growing tumor is always accompanied by excessive angiogenesis. Such a pathological change gives rise to leaky vasculature and poorly organized lymphatic system, which favors enhanced permeability and retention (EPR, also known as passive targeting) in the tumor tissue for

5. BRINGING AIE INTO IN VIVO BIOIMAGING In vivo FL imaging is a pivotal tool to get deep insights into intact and native physiological processes and diseased states.224 Unlike fluorescence microscope that typically deals with cellular samples cultured under simulated biological fluids, this technique works at the macroscopic level and allows for the characterization of the whole body of small animals under physiological conditions. To overcome photon attenuation via either absorption or scattering as well as autofluorescence from endogenous chromophores in living tissues (e.g., flavin adenine dinucleotide, nicotinamide adenine dinucleotide, and amino acids containing aromatic structures),225,226 two general strategies have been proposed. On the one hand, novel bioprobes with superior physicochemical properties and smart structural design have been developed. First, luminogens with emission spectra locating at the NIR regions are synthesized to offer deep penetration due to the minimized interactions between photons and native tissues. Two NIR regions are generally identified for biological imaging, including NIR-I (700−900 nm, with reduced tissue absorption) and NIR-II (1000−1700 nm, with reduced photon scattering and tissue autofluorescence), in which the NIR-II subwindows, including NIR-IIa (1300−1400 nm) and NIR-IIb (1500−1700 nm), G

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Figure 5. Schematic illustration showing the applications of related photophysical and photochemical processes for disease theranostics.

nanoparticles with appropriate sizes (e.g., 50−200 nm).241 To facilitate the active uptake of nanoparticles by cancer cells, a variety of targeting moieties can be used to decorate the nanoparticles for selective binding with specific receptors that are over-expressed in cancer cells (also known as active targeting).241,256 Because most studied models are subcutaneous tumor xenografts that are grown from implanted cancer cells, AIEgen-based bioprobes with far-red/NIR emissions are potent enough to achieve high-quality in vivo tumor imaging.34,86,94,187,242,243 In view of the implications of vascular structural change or dysfunction for many diseases (e.g., cardiovascular disease), the establishment of an efficient in vivo angiography technique for real-time monitoring with high accuracy and tempo-spatial resolution is quite helpful for clinicians to accurately identify pathological processes.52,55 To get deep penetration into living tissues and visualize the subtle structures of blood vessels, the use of AIEgen-based bioprobes with long NIR emissions42,97 and multiphoton techniques35,209,247−254 are demonstrated to be successful. Aside from these two in vivo applications, it is also feasible to use AIEgen-based bioprobes for sentinel lymph node (SLN) imaging,36,54,90 inflammation imaging,91,101,245,257 apoptosis imaging,165,258 long-term tracking,204,207,244 and blood−brain barrier (BBB) imaging.254,259 In contrast to single-modality imaging, AIEgen-based multimodality imaging that integrates two or more imaging modalities provides a better solution to overcome the limitations of individual techniques and is promising for accurate identification of injured and diseased tissues. Despite currently combined modalities are only limited to computed tomography (CT),260,261 magnetic resonance imaging (MRI),262,263 PA imaging,97,104 and dark-field imaging,261 more advanced modalities are anticipated to be introduced to further expand the scope of available information. For detailed cases regarding in vivo bioimaging, it is recommended to refer to Table S3.

6. BRINGING AIE INTO CANCER THERANOSTICS Cancer theranostics refers to the combination of cancer diagnostics and therapeutics, the aim of which is to achieve accurate molecular imaging for early diagnosis and precise treatment for efficient therapy as well as real-time monitoring of therapeutic efficacy.264−266 Because the successful application of cancer theranostics significantly relies on the appropriate use of multifunctional materials, the development of efficient theranostic agents paves a way to boost precision medicine. Considering the numerous merits of FL imaging, image-guided cancer therapy can provide clinicians with an indepth understanding of the pathological state of neoplastic tissues as well as the guidance of appropriate actions for personalized cancer therapy.94 The associated photophysical processes of AIEgen-based materials for cancer theranostics can be clarified by the simplified Jablonski diagram as shown in Figure 5.41,267 Upon the absorption of photons with an appropriate energy, electrons in the singlet ground state (S0) are excited to higher-energy orbitals. Based on the Kasha’s rule, the lowest excited singlet state (S1), in most cases, involves in the subsequent photophysical processes. Basically, there are four deactivation routes to consume the excitation energy. First, the radiative transition from S1 to S0 leads to the release of fluorescence, which is used for fluorescence-based molecular imaging as well as fluorescence imaging-guided therapy. Second, heat energy is generated during the non-radiative transition from S1 to S0 via internal conversion, which can be directly used for PTT. Meanwhile, the production of heat results in transient thermoelastic expansion and thus emission of wideband ultrasonic waves for PA imaging. Third, efficient intersystem crossing (ISC) from S1 to excited triplet state (T1) takes place when the singlet−triplet energy gap is sufficiently small. In the following step, phosphorescence is generated via radiative decay from T1 to S0. Because the transition between triplet and singlet states is kinetically unfavored in quantum mechanics, T1 typically exhibits a long lifetime, ranging from microseconds to seconds, which is promising for ultra-sensitive H

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7. CONCLUDING REMARKS AND FUTURE PERSPECTIVES In this work, we systematically reviewed the trailblazing journey of AIE in the field of biomedicine, with an emphasis on the working principles and general strategies on the design and fabrication of AIEgen-based materials for biomacromolecule sensing, in vitro cell imaging, in vivo bioimaging, and cancer theranostics. Enabled by the collaborations among a variety of disciplines, the past 18 years have witnessed huge advancements in using versatile AIEgens for diverse biomedical applications. Specifically, the objects of study have been expanded from metal ions, small molecules, and biomacromolecules in simple buffered systems to prokaryotes, eukaryotes, and even animals with complicated biological fluids. The imaging modalities have been extended to cover one-photon fluorescence imaging, multiphoton fluorescence imaging, Raman imaging, MRI, CT, and PA imaging for accurate, real-time, and high-quality diagnosis. The utilized strategies for cancer treatment have been broadened from chemotherapy, PDT, gene delivery, and PTT to multimodal therapy that combines two or more of these strategies to achieve synergistc effects of “1 + 1 > 2”. All of these achievements indicate the persistent vitality of AIEgens for the investigation of various biomedical issues. Looking ahead, we conceive that the following aspects could be considered to further flourish AIEgen-based biosystems. First, despite a myriad of AIEgen-based bioprobes have been harnessed to interact with mammalian cells for cell imaging, the exact mechanisms of how these probes enter intracellular space remain elusive. It is thus urgent to answer this critical question so as to facilitate the design of next-generation bioprobes for improved intracellular performance. Second, the development of AIEgen-based systems with multifunctional components is capable of offering diverse theranostic functions. However, increased components typically indicate decreased translational potential. It is thus preferred to develop single-molecule systems with transformable photophysical and photochemical behaviors or balanced proportion among different photophysical processes. Only when the desired functionalities are unable to be provided by single-molecule systems should one turn to the simultaneous incorporation of multiple theranostic agents. Third, despite researchers starting to boost the discovery of natural molecules with AIE properties for biomedical applications, the overall quantity remains limited. As such, the development of more natural AIEgens is still needed. Fourth, in addition to the widely investigated cancer, the research topics of AIE in the biomedical field should be further expanded. For instance, AIEgen-based bioprobes have been evidenced to be able to track the fate and regenerative capability of stem cells. As another research frontier, it is also feasible to combine AIEgens with stem-cellbased scaffolds to understand how the cells interact with their residing microenvironment and decipher how the microenvironment intervenes or guides stem cell differentiation. Fifth, although the possibilities of AIEgen-based bioprobes have been demonstrated in a series of imaging modalities, more-advanced modalities together with activatable contrast agents are still desired for further integration, such as (i) fluorescence lifetime imaging using AIEgens with long fluorescence lifetime and time-resolved photoluminescence using AIEgens with delayed fluorescence298 or ultralong phosphorescence299 for precise in vivo imaging without

in vivo afterglow imaging (i.e., the collection of signals after cessation of light irradiation). Fourth, the long-lived T1 is also potent enough to interact with adjacent triplet oxygen (3O2) via energy transfer to produce highly reactive singlet oxygen (1O2), which is able to react with various biological species (e.g., lipids and proteins) to inactivate their biological functions. In addition, T1 can directly transfer electrons to surrounding cellular components, leading to the formation of radicals and reactive oxygen species (ROS). The resultant reactive species through either photochemical pathway are able to cause severe cell damages, thereby enabling the application of PDT. Based on the aforementioned photophysical and photochemical processes, AIEgens have been integrated into various systems for cancer theranostics. First, AIEgens are covalently conjugated with (pro-)drugs (e.g., doxorubicin,268−270 cisplatin,112,268,271 and camptothecin)272 or noncovalently encapsulated with (pro-)drugs into nanoparticles273−275 for monitoring real-time drug distribution and release for image-guided chemotherapy. In some particular cases, AIEgens themselves exhibit intrinsic therapeutic effects by disrupting normal metabolic activities of cells.93,162,276−279 To decrease or even quench the original fluorescence of AIEgens, the design of water-soluble AIEgen-(pro)drug conjugates112,271 and AIEgenbased fluorescence resonance energy-transfer systems268−270,273 have been employed. In this case, in situ production and the release of drugs can be visualized by monitoring fluorescence recovery of AIEgens or analyzing ratiometric fluorescence changes between AIEgens and fluorescent drugs. Second, different from classic ACQ photosensitizers, the non-radiative pathway of aggregated AIEgens is significantly blocked, leading to the efficient utilization of both radiative fluorescence and triplet-state species for image-guided PDT. Mostly, AIEgen-based bioprobes are directly used for PDT.43,95,134,137,139,142,157,168,253,280−284 In some cases, the AIEgens are combined with traditional photosensitizers to fluorescently monitor the process of PDT.246,285 In recent studies, the incorporation of AIEgens and peroxalates is also explored for the illumination-free production of ROS via a chemically initiated electron exchange luminescence process between high-energy intermediates and AIEgens.101 Third, AIEgen-based bioprobes can serve as a positively charged matrix to bind with negatively charged genetic materials (e.g., DNA or siRNA) via electrostatic adsorption for image-guided gene therapy.102,286−288 Once delivered into mammalian cells, these genetic materials either silence the expression of diseased proteins or induce the expression of therapeutic proteins. Fourth, AIEgens with rotor-like structures typically show negligible fluorescence when existing as molecularly dissolved species. In this case, non-radiative decay dominates the relaxation of excitons, making AIEgens a class of promising materials for PTT.37,289 Besides, combination therapy that utilizes more than one medication or modalities has been recognized as a promising strategy because it can provide a significantly enhanced therapeutic index over any monotherapy (i.e., synergistic effects).290 Such a concept is also harnessed by various AIEgen-based bioprobes for enhanced cancer therapy.291−297 A comprehensive summary of the AIEgens that have been designed for cancer theranostics can be found in Table S4. I

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M.; Megason, S. G.; Kirchhausen, T.; Betzig, E. Observing the Cell in its Native State: Imaging Subcellular Dynamics in Multicellular Organisms. Science 2018, 360, eaaq1392. (5) Chen, G.; Huang, A. C.; Zhang, W.; Zhang, G.; Wu, M.; Xu, W.; Yu, Z.; Yang, J.; Wang, B.; Sun, H.; Xia, H.; Man, Q.; Zhong, W.; Antelo, L. F.; Wu, B.; Xiong, X.; Liu, X.; Guan, L.; Li, T.; Liu, S.; Yang, R.; Lu, Y.; Dong, L.; McGettigan, S.; Somasundaram, R.; Radhakrishnan, R.; Mills, G.; Lu, Y.; Kim, J.; Chen, Y. H.; Dong, H.; Zhao, Y.; Karakousis, G. C.; Mitchell, T. C.; Schuchter, L. M.; Herlyn, M.; Wherry, E. J.; Xu, X.; Guo, W. Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response. Nature 2018, 560, 382−386. (6) Miller, C. N.; Proekt, I.; von Moltke, J.; Wells, K. L.; Rajpurkar, A. R.; Wang, H.; Rattay, K.; Khan, I. S.; Metzger, T. C.; Pollack, J. L.; Fries, A. C.; Lwin, W. W.; Wigton, E. J.; Parent, A. V.; Kyewski, B.; Erle, D. J.; Hogquist, K. A.; Steinmetz, L. M.; Locksley, R. M.; Anderson, M. S. Thymic Tuft Cells Promote an IL-4-Enriched Medulla and Shape Thymocyte Development. Nature 2018, 559, 627−631. (7) Gonçalves, M. S. T. Fluorescent Labeling of Biomolecules with Organic Probes. Chem. Rev. 2009, 109, 190−212. (8) Yang, Q.; Ma, Z.; Wang, H.; Zhou, B.; Zhu, S.; Zhong, Y.; Wang, J.; Wan, H.; Antaris, A.; Ma, R.; Zhang, X.; Yang, J.; Zhang, X.; Sun, H.; Liu, W.; Liang, Y.; Dai, H. Rational Design of Molecular Fluorophores for Biological Imaging in the NIR-II Window. Adv. Mater. 2017, 29, 1605497. (9) Zhang, S.; Guo, W.; Wei, J.; Li, C.; Liang, X.-J.; Yin, M. Terrylenediimide-Based Intrinsic Theranostic Nanomedicines with High Photothermal Conversion Efficiency for Photoacoustic ImagingGuided Cancer Therapy. ACS Nano 2017, 11, 3797−3805. (10) Zhu, C.; Liu, L.; Yang, Q.; Lv, F.; Wang, S. Water-Soluble Conjugated Polymers for Imaging, Diagnosis, and Therapy. Chem. Rev. 2012, 112, 4687−4735. (11) Wang, Y.; Li, S.; Zhang, P.; Bai, H.; Feng, L.; Lv, F.; Liu, L.; Wang, S. Photothermal-Responsive Conjugated Polymer Nanoparticles for Remote Control of Gene Expression in Living Cells. Adv. Mater. 2018, 30, 1705418. (12) Guo, B.; Sheng, Z.; Hu, D.; Li, A.; Xu, S.; Manghnani, P. N.; Liu, C.; Guo, L.; Zheng, H.; Liu, B. Molecular Engineering of Conjugated Polymers for Biocompatible Organic Nanoparticles with Highly Efficient Photoacoustic and Photothermal Performance in Cancer Theranostics. ACS Nano 2017, 11, 10124−10134. (13) Li, D.; Gao, D.; Qi, J.; Chai, R.; Zhan, Y.; Xing, C. Conjugated Polymer/Graphene Oxide Complexes for Photothermal Activation of DNA Unzipping and Binding to Protein. ACS Appl. Bio Mater. 2018, 1, 146−152. (14) Michalet, X.; Pinaud, F. F.; Bentolila, L. A.; Tsay, J. M.; Doose, S.; Li, J. J.; Sundaresan, G.; Wu, A. M.; Gambhir, S. S.; Weiss, S. Quantum Dots for Live Cells, In Vivo Imaging, and Diagnostics. Science 2005, 307, 538−544. (15) Bruns, O. T.; Bischof, T. S.; Harris, D. K.; Franke, D.; Shi, Y.; Riedemann, L.; Bartelt, A.; Jaworski, F. B.; Carr, J. A.; Rowlands, C. J.; Wilson, M. W. B.; Chen, O.; Wei, H.; Hwang, G. W.; Montana, D. M.; Coropceanu, I.; Achorn, O. B.; Kloepper, J.; Heeren, J.; So, P. T. C.; Fukumura, D.; Jensen, K. F.; Jain, R. K.; Bawendi, M. G. NextGeneration In Vivo Optical Imaging with Short-Wave Infrared Quantum Dots. Nat. Biomed. Eng. 2017, 1, 0056. (16) Haase, M.; Schäfer, H. Upconverting Nanoparticles. Angew. Chem., Int. Ed. 2011, 50, 5808−5829. (17) Wang, F.; Liu, X. Upconversion Multicolor Fine-Tuning: Visible to Near-Infrared Emission from Lanthanide-Doped NaYF4 Nanoparticles. J. Am. Chem. Soc. 2008, 130, 5642−5643. (18) Chen, S.; Weitemier, A. Z.; Zeng, X.; He, L.; Wang, X.; Tao, Y.; Huang, A. J. Y.; Hashimotodani, Y.; Kano, M.; Iwasaki, H.; Parajuli, L. K.; Okabe, S.; Teh, D. B. L.; All, A. H.; Tsutsui-Kimura, I.; Tanaka, K. F.; Liu, X.; McHugh, T. J. Near-Infrared Deep Brain Stimulation via Upconversion Nanoparticle−Mediated Optogenetics. Science 2018, 359, 679−684.

autofluorescence interferences and (ii) noninvasive nuclear medicine imaging (e.g., positron emission computed tomography) for the early identification of diseases and monitoring immediate responses of therapeutic interventions. Last, despite most in vitro and in vivo studies indicating the biocompatibility of AIEgen-based bioprobes, it is still essential to perform long-term toxicological evaluations using animal models to accelerate their clinical translation. We believe that AIEgens will play vital roles in the exploration of mysterious life processes by integration with various cutting-edge modalities and techniques, with an ultimate goal of addressing more healthcare issues. It is hoped that this review will inspire more scientific researchers from diverse disciplines to engage in such an enthusiastic and viable research field and altogether promote the translation of AIEgen-based materials for widespread clinical use.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00600. Tables summarizing the use of AIEgen-based bioprobes for various biomedical applications and all related references (PDF)



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chunlei Zhu: 0000-0003-2477-306X Ryan T. K. Kwok: 0000-0002-6866-3877 Ben Zhong Tang: 0000-0002-0293-964X Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation of China (grant no. 21788102), the Research Grants Council of Hong Kong (grant nos. 16308016, 16305015, 16305518, C2014-15G, C6009-17G, and AHKUST605/16), the Innovation and Technology Commission (grant nos. ITC−CNERC14SC01 and ITS/254/17), and the Science and Technology Plan of Shenzhen (grant nos. JCYJ20160229205601482 and JCYJ20170818113602462). C.Z. is grateful for the support from the Thousand Talents Program for Young Professionals.



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Review

ACS Applied Bio Materials

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DOI: 10.1021/acsabm.8b00600 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

Review

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DOI: 10.1021/acsabm.8b00600 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

Review

ACS Applied Bio Materials (293) Wang, K.; Fan, X.; Zhao, L.; Zhang, X.; Zhang, X.; Li, Z.; Yuan, Q.; Zhang, Q.; Huang, Z.; Xie, W.; Zhang, Y.; Wei, Y. Aggregation Induced Emission Fluorogens Based Nanotheranostics for Targeted and Imaging-Guided Chemo-Photothermal Combination Therapy. Small 2016, 12, 6568−6575. (294) Chen, C.; Song, Z.; Zheng, X.; He, Z.; Liu, B.; Huang, X.; Kong, D.; Ding, D.; Tang, B. Z. AIEgen-Based Theranostic System: Targeted Imaging of Cancer Cells and Adjuvant Amplification of Antitumor Efficacy of Paclitaxel. Chem. Sci. 2017, 8, 2191−2198. (295) Feng, G.; Liu, J.; Zhang, C.-J.; Liu, B. Artemisinin and AIEgen Conjugate for Mitochondria-Targeted and Image-Guided Chemoand Photodynamic Cancer Cell Ablation. ACS Appl. Mater. Interfaces 2018, 10, 11546−11553. (296) Jin, G.; Feng, G.; Qin, W.; Tang, B. Z.; Liu, B.; Li, K. Multifunctional Organic Nanoparticles with Aggregation-Induced Emission (AIE) Characteristics for Targeted Photodynamic Therapy and Rna Interference Therapy. Chem. Commun. 2016, 52, 2752− 2755. (297) Li, Q.-L.; Wang, D.; Cui, Y.; Fan, Z.; Ren, L.; Li, D.; Yu, J. AIEgen-Functionalized Mesoporous Silica Gated by CyclodextrinModified Cus for Cell Imaging and Chemo-Photothermal Cancer Therapy. ACS Appl. Mater. Interfaces 2018, 10, 12155−12163. (298) Ni, F.; Zhu, Z.; Tong, X.; Xie, M.; Zhao, Q.; Zhong, C.; Zou, Y.; Yang, C. Organic Emitter Integrating Aggregation-Induced Delayed Fluorescence and Room-Temperature Phosphorescence Characteristics, and its Application in Time-Resolved Luminescence Imaging. Chem. Sci. 2018, 9, 6150−6155. (299) Zhang, K. Y.; Yu, Q.; Wei, H.; Liu, S.; Zhao, Q.; Huang, W. Long-Lived Emissive Probes for Time-Resolved Photoluminescence Bioimaging and Biosensing. Chem. Rev. 2018, 118, 1770−1839.

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DOI: 10.1021/acsabm.8b00600 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX