Nanozymes: Classification, Catalytic Mechanisms, Activity Regulation

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

Nanozymes: Classification, Catalytic Mechanisms, Activity Regulation, and Applications Yanyan Huang,†,‡ Jinsong Ren,† and Xiaogang Qu*,† †

Chem. Rev. Downloaded from pubs.acs.org by UNIV OF SUSSEX on 02/25/19. For personal use only.

Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China ‡ College of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing 210037, China ABSTRACT: Because of the high catalytic activities and substrate specificity, natural enzymes have been widely used in industrial, medical, and biological fields, etc. Although promising, they often suffer from intrinsic shortcomings such as high cost, low operational stability, and difficulties of recycling. To overcome these shortcomings, researchers have been devoted to the exploration of artificial enzyme mimics for a long time. Since the discovery of ferromagnetic nanoparticles with intrinsic horseradish peroxidase-like activity in 2007, a large amount of studies on nanozymes have been constantly emerging in the next decade. Nanozymes are one kind of nanomaterials with enzymatic catalytic properties. Compared with natural enzymes, nanozymes have the advantages such as low cost, high stability and durability, which have been widely used in industrial, medical, and biological fields. A thorough understanding of the possible catalytic mechanisms will contribute to the development of novel and high-efficient nanozymes, and the rational regulations of the activities of nanozymes are of great significance. In this review, we systematically introduce the classification, catalytic mechanism, activity regulation as well as recent research progress of nanozymes in the field of biosensing, environmental protection, and disease treatments, etc. in the past years. We also propose the current challenges of nanozymes as well as their future research focus. We anticipate this review may be of significance for the field to understand the properties of nanozymes and the development of novel nanomaterials with enzyme mimicking activities.

CONTENTS 1. Introduction 2. Classification of Nanozymes 3. Catalytic Mechanism of Nanozymes 3.1. Oxidase Family 3.1.1. Glucose Oxidase 3.1.2. Sulfite Oxidase 3.2. Peroxidase Family 3.2.1. Peroxidase 3.2.2. Glutathione Peroxidase 3.2.3. Haloperoxidase 3.3. Catalase 3.4. Superoxide Dismutase 3.5. Others 4. Tuning the Catalytic Activities of Nanozymes 4.1. Size 4.2. Morphology 4.3. Surface Modification 4.4. Composition 4.5. Constructing Hybrid Nanomaterials 4.6. pH and Temperature 4.7. Ions or Molecules 4.8. Light 5. Recent Research Process of Nanozymes 5.1. Nanozymes in Sensing 5.1.1. Detection of Ions © XXXX American Chemical Society

5.1.2. Detection of Molecules 5.1.3. Detection of Nucleic Acids 5.1.4. Detection of Proteins 5.1.5. Detection of Cancer Cells 5.2. Nanozymes in Environmental Treatment 5.2.1. Nanozymes in Degrading Organic Pollutants in Wastewater 5.2.2. Nanozymes in Degrading Chemical Warfare Agents 5.2.3. Nanozymes in Inhibiting Biofilm Formation 5.3. Nanozymes in Antibacteria and Cancer Treatment 5.3.1. Nanozymes in Antibacteria 5.3.2. Nanozymes in Cancer Therapy 5.4. Nanozymes in Antioxidation 5.4.1. Nanozymes in Cytoprotection 5.4.2. Nanozymes in Alleviating Inflammation 5.4.3. Nanozymes in Treating Alzheimer’s Disease 5.4.4. Nanozymes in Treating Parkinson’s Disease 5.5. Other Applications

B G G G G H H H I J J J J K L L L N N O O O Q Q Q

R S S T U U U V W W Z AA AB AD AE AF AG

Received: November 10, 2018

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DOI: 10.1021/acs.chemrev.8b00672 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 5.5.1. Nanozymes in Imaging 5.5.2. Antithrombosis 5.5.3. Individual Living Cell Encapsulation 5.5.4. Bioorthogonal Catalysis 5.5.5. Treating Hyperuricemia 5.5.6. UV-Protective Sunscreens 6. Conclusions and Prospects Author Information Corresponding Author ORCID Notes Biographies Acknowledgments Abbreviations References

Review

of these novel properties, nanozymes have been utilized for biosensing,46−48 environmental treatment,49,50 disease diagnosis and treatment,51−53 antibacterial agents,54−57 and cytoprotection against biomolecules in the cell,58−60 and so on (Figure 1).

AG AH AH AI AI AI AI AJ AJ AJ AJ AJ AJ AJ AL

1. INTRODUCTION Enzymes, as powerful biocatalysts, are mainly composed of proteins while a few are catalytic RNA molecules.1,2 Whereas typical chemical catalysts or industrial catalysts are often used in harsh conditions such as high temperature, high pressure, organic solvents, as well as extreme pH surroundings,3,4 enzymes are mainly used to catalyze the conversion of biomolecules, and these reactions are usually carried out under relatively mild conditions.5,6 Because of the high catalytic activities and substrate specificity,7,8 natural enzymes have been widely used in industrial, medical, and biological fields.9−12 Although promising, they often suffer from intrinsic shortcomings such as high cost for preparation and purification, low operational stability, sensitivity of catalytic activity to environmental conditions, and difficulties in recycling and reusing.13,14 These disadvantages all limit their further applications in food processing, biosensing, environmental protection, biomedicine, and so on. To overcome these drawbacks, researchers have been devoted to the exploration of artificial enzyme mimics for a long time.15−17 Previously, studies have demonstrated that a variety of materials could serve as artificial enzymes with similar structures and functions, such as, fullerenes, cyclodextrins, polymers, dendrimers, porphyrins, metal complexes, and some biomolecules.18−24 Since the discovery of Fe3O4 nanoparticles as peroxidase mimics in 2007,25 a large amount of studies on nanomaterialbased artificial enzymes (named as “nanozymes”)26−30 have been constantly emerging.31−39 Nanozymes are one kind of nanomaterials40,41 with nanoscale sizes (1−100 nm) and enzymatic catalytic properties. They can be divided into two categories: (1) enzymes or enzymatic catalytic groups which are modified on nanomaterials, named nanomaterial hybrid enzymes. With the assistance of nanomaterials, the modified enzymes or enzymatic catalytic groups can achieve enhanced stability as well as durability. (2) Nanomaterials possess the inherent enzymatic catalytic properties which display a similar mechanism as enzymes to catalyze the same biocatalytic reactions.42 Nanozymes successfully combine the properties of typical chemical catalysts and biocatalysts. Recent research is mainly focused on the exploration of nanomaterials with inherent catalytic capacities since it is an attractive field to achieve the potential applications of nanomaterials. Compared with natural enzymes, nanozymes have the advantages such as low cost, high stability, and durability.26−28,42 More interestingly, some nanozymes can also catalyze some non-natural bioprocesses such as bioorthogonal catalysis.43−45 On the basis

Figure 1. Recent applications of nanozymes in biosensing (Reprinted from ref 62. Copyright 2017 American Chemical Society), environmental treatment, antibacteria, cancer therapy (Reprinted with permission from ref 97. Copyright 2018 Nature Publishing Group), and cytoprotection (Reprinted with permission from ref 605. Copyright 2017 Wiley-VCH).

Until the date, many nanomaterials have been uncovered, which possess remarkable enzyme-like activities. For example, Fe3O4 nanoparticles,25,61 Au nanoparticles,31,62,63 graphene oxide (GO) nanosheets,36 polypyrrole nanoparticles,64 etc. have been shown to possess a unique peroxidise-like property. Studies also demonstrate that Pt nanoparticles,65,66 Pd nanomaterials,67 CeO2,68−70 and MnO260,71 nanoparticles have inherent catalase (CAT) and superoxide dismutase (SOD)-mimic abilities. In addition, Au nanoparticles can mimic glucose oxidase (GOx) to catalyze the oxidation of glucose to produce gluconic acid.72 When coupled to a recent exciting discovery from Mugesh and co-workers, who demonstrated that V2O5 nanowires had unique glutathione peroxidise (GPx)-like activity to detoxify harmful H2O2 with the assistance of glutathione (GSH),33 these findings can not only promote the development of nanozymes but also deepen our understandings for natural enzymes. The rapid development of nanotechnology has broadened the way of exploration of novel nanozymes. Combined with computer simulation and theoretical calculation, the possible catalytic mechanisms of nanozymes have been gradually unraveled. These studies may contribute to the improvement of the catalytic activities of nanozymes. On the basis of biomedical technology, nanozymes have gradually exhibited advantages in the field of disease diagnosis and treatment. Although several excellent reviews focused on nanozymes have been reported,26−30 some of them just reviewed one kind of nanomaterials as enzyme mimics, while other reviews are mainly concentrated on certain specific topics. Up to now, few in-depth reviews discuss the potential applications of nanozymes in detail. What’s more, little attention has been focused on the detailed classification and catalytic mechanisms of nanozymes. Herein, we present a comprehensive review to introduce the classification, catalytic mechanism, activity B


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Table 1. Current Nanomaterials As Enzyme Mimics and Their Typical Applications and Representative References enzyme oxidoreductive family oxidases oxidase

nanomaterial

reference

application

Au Ag Pt Pd Ir Ru MSN-Au Au@Pt Au@PdPt PtCo PtCo@MnO2 NiPd GQD/Ag FeNPs/NC Fe3C@C N-CNMs Se Pt−Se ZnO CeO2 CeO2/rGO MnO2 Mn3O4 V6O13 CoFe2O4 MnFe2O4 NiCo2O4 Ce-MOF Co/2Fe MOF Ag-CoFe2O4/rGO

81, 82 83 84 81 85 86 87 88, 89 90 91 92 93 94 95 96 97 98 99 100 32, 101−103 104 105−107 109 110 111 112 113 114, 115 116 117

− detection − − detection − antibacteria immunoassay − detection cancer therapy detection antibacteria detection − cancer therapy − detection detection detection detection immunodetection detection detection detection − detection detection detection detection

glucose oxidase

Au EMSN-Au Fe3O4-Au@MS Au-MOF TiO2-AuNRs

63, 118, 119 120, 121 122 123 124

detection − − detection −

cytochrome c

Cu2O

125

−

laccase

Cu/GMP MOF Cu-CDs

126 127

− −

sulfite oxidase

MoO3

37

cytoprotection

nitric oxide synthase

grapheme-hemein

128

antithrombosis

ascorbate oxidase

Au@Pt

129

detection

Au Ag Pt Pd Cu Ir Ru

82, 130−132 133 134, 135 136 137 138 139

detection detection detection detection detection detection −

oxidase

peroxidases horseradish peroxidase

C


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Table 1. continued enzyme

nanomaterial

reference

EMSN-Au Au@Ag Au@Pt Au@Pd Au-MOF Au/CuS Au/g-C3N4 Au/Co3O4−CeOx Au/Fe3O4/GO Au−Pd−Fe3O4/rGO Pd-Ir Bi/Au Bi/Pt AgM (Au, Pd, Pt) PtCu Pt@mSiO2 Pt-MoO3 PtNPs/GO PtPdNDs/GNs BiFeO3 CuO CuO/Pt CuS Cu(OH)2 Cu NPs@C CuInS2 Cu2+-GO Cu2+-g-C3N4 Cu2+-C-dots BSA-Cu3(PO4)2 Fe3O4 γ-Fe2O3 Fe1−xMnxFe2O4 FePO4 FeVO4 FeS Fe3S4 FeSe FeTe FeNPs@Co3O4 FePt/GO PB PB/PPy PB/MWCNT PB/γ-Fe2O3 Fe3O4@C Fe3O4@GO Fe3O4@ 3D GN Fe3O4@GO@Pt Fe3O4-MWCNT Fe3O4-MMT γ-Fe2O3/SiO2 γ-FeOOH/rGO FeOOH/N-carbon FeMnO3@PPy Fe2(MoO4)3 V2O5 VO2 V6O13 VOx V2O3-OMC

72 140 88, 129 141 62 142 143 144 145 146 147 148 149 150, 151 152 153 154 155 156 157 158 159 160, 161 162 163 164 165 166 166 167 25, 168−170 171 172 173 174 175 176 177 178 179 180 181, 182 183 184, 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 110 200, 201 202 D

application − immunoassay immunoassay immunoassay detection − antibacteria detection detection − immunoassay detection detection detection phenol degradation immunoassay detection detection detection detection phenol degradation detection immunodetection − detection detection detection detection detection immunodetection cancer therapy immunoassay detection detection detection detection detection detection detection detection detection detection detection MB degradation detection detection detection − water purification detection detection phenol degradation detection detection detection − − detection detection detection DOI: 10.1021/acs.chemrev.8b00672 Chem. Rev. XXXX, XXX, XXX−XXX

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nanomaterial

reference

CeO2 Cu2(OH)3Cl-CeO2 GO@SiO2@CeO2 Co3O4@CeO2 Fe3O4@CeO2 TiO2@CeOx CePO4:Tb CePO4:Tb,Gd ATP-Ce-tris CPNs CoP Co3O4 CoFe2O4 CoFe2O4/cyclodex CoFe-LDHs MnO2 MnSe MnSe-g-C3N4 MnFe2O4 MoS2 MoS2-Pt74Ag26 MoS2-ppy-Pd ZnO ZnO-CNTs ZnFe2O4 ZnFe2O4-ZnO porphyrin-ZnS Zn-CuO AgVO3 WSe2 PtPd-Fe3O4 polypyrrole SWNTs SWCNHs-COOH MWCNT@rGONR N-CNMs GO-COOH GO-AuNC polyoxometalate FF@PW12@GO graphene-hemin graphene-ferric porphyrin GCNT-Fe3O4 hemin-SWCNT hemin-micelle Co3O4/rGO Cu-Ag/rGO Ag-Cu2O/rGO GQDs GQDs/CuO CQDs CNDs CNTs CdTe QDs CFMP g-C3N4 g-C3N4/BiFeO3 Co-g-C3N4 Si-dots metalloporphyrinic MOFs Fe-MOF E

application

203−205 206 207 208 209 210 211 212 213 214 215 216 217 218 106 219 220 221 222 223 224 225, 226 227 228 229 230 231 232 233 234 64, 235 236 237 238 97 239 240 241−244 245 246 247 248 249 250 251 252 253 254, 255 256 257−259 260 261 262 263 264 265 266 267 268, 269

detection detection detection detection detection − detection imaging detection detection detection detection detection detection immunoassays detection detection immunoassays antibacteria detection detection detection detection detection detection detection detection detection detection detection detection detection detection detection cancer therapy detection detection detection detection detection detection detection detection detection detection detection detection detection detection detection detection antibacteria − detection detection immunoassays wastewater treatment detection −

270, 271

detection DOI: 10.1021/acs.chemrev.8b00672 Chem. Rev. XXXX, XXX, XXX−XXX

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nanomaterial

reference

application

Cu-MOF Ni-MOF Pt-MOF Co/2Fe MOF Hemin-MOF Cu-hemin MOFs POM-MOFs Se fluorescein NiPd

272, 273 274 275 116 276, 277 278 279 280 281 93, 282

detection detection detection, Hg2+ removal detection detection detection detection green synthesis − detection

glutathione peroxidase

V2O5 Se Se-CQDs GO-Se GOSe Se@pDA Se-MOF Te Mn3O4

33, 283 284, 285 286 287 288 289 290 291 108

antioxidant antioxidant antioxidant, imaging antioxidant antioxidant antioxidant − antioxidant antioxidant

haloperoxidase

V2O5 CeO2−x

34 292

antibacteria antibacteria

NADH peroxidase

Cu2+-GO

165

−

catalase

Au Ag Pt Pd Ir BSA-IrO2 Au@Pt CeO2 MnO2 Mn3O4 Fe3O4 α-Fe2O3 γ-Fe2O3 Co3O4 PB VOx V6O13 NiPd N-CNMs GOQDs LaNiO3 Pt-MOF

293 294 66 67 295 296 297 298 71 59, 299 300 301 171 215, 302 39 201 110 93 97 303 304 65

antioxidant − − antioxidant antioxidant cancer therapy detection antioxidant antioxidant antioxidant antioxidant antioxidant antioxidant detection antioxidant − − − − antioxidant detection cancer therapy

superoxide dismutase

Au Pt Pd fullerene PEG-HCCs GOQDs CeO2 Au/CeO2 MnO2 Mn3O4 Mn-NPs FePO4

81 305 67 306−308 309 303 310−313 314 71 108, 299 315 316

− − antioxidant − − antioxidant antioxidant − antioxidant antioxidant − −

F


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nanomaterial

reference

application

PB PB-NGS N-CNMs Ceria/POMs AuNPs@POMD-8pe p Gly-Cu(OH)2

39, 317 318 97 319 320

antioxidant − − antioxidant antioxidant

321

antioxidant

CdS-Pt

322

−

Au DMAE

82 323

− antibacteria

esterase

Au

82, 324

−

phosphatase

CeO2 VE CeO2

325, 326 327

MOF-CeO2

328

detection degradation of nerve agents −

protease

CeONP@POMs AuNPs@POMD-8pe p

319 320

AD therapy AD therapy

silicatein

Au

82

−

urease

CeO2−x

329

−

nitrate reductase hydrolase family nuclease

their typical applications. This classification may help us better understand nanozymes.

regulation, and recent research progress of nanozymes in the past years. The current challenges and future prospects of nanozymes are also summarized and discussed. We anticipate that the present timely review will be of significant benefit for the field in order to understand the properties of nanozymes to a greater level and to further-develop novel nanomaterial with enzyme mimicking activities by attracting researchers from different disciplines, including chemistry, biology, materials science, and nanotechnology.

3. CATALYTIC MECHANISM OF NANOZYMES In recent years, although nanozymes have received extensive attention, the study of their catalytic mechanisms as well as kinetics are still not thorough. In this section, we summarize the mechanisms and kinetics of typical nanozymes with unique catalytic activities. We will analyze the catalytic mechanisms and kinetics according to the types of enzymes.

2. CLASSIFICATION OF NANOZYMES A series of enzymes have been discovered in living systems.73−77 They participate in complicated biocatalytic processes individually or together and play important roles in life progresses.78−80 Considering the importance of natural enzymes in the life system and their intrinsic drawbacks, it is of great significance to explore their alternatives. Thanks to the sustained efforts of researchers, a lot of nanomaterials have served as potential enzyme candidates for practical applications.26−39 In this part, in order to get a clearer understanding, we divide nanozymes into 2 categories: (1) oxidoreductase family, for example, oxidase, peroxidase, catalase, superoxide dismutase, and nitrate reductase, and (2) hydrolase family, including nuclease, esterase, phosphatase, protease, and silicatein (Table 1). For example, graphene and carbon nanotube have been demonstrated to possess excellent peroxidase-like property to catalyze the oxidation of many substrates such as 3,3′,5,5′-tetramethylbenzidine (TMB) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) in the presence of H2O2. We systematically and comprehensively list the current nanomaterials with catalytic activities and

3.1. Oxidase Family

3.1.1. Glucose Oxidase. In 2004, Rossi and colleagues proposed that “naked” gold nanoparticles could catalyze glucose to generate gluconic acid and H2O2 in the presence of O2.330 Control experiments demonstrated that other metal nanomaterials did not show obvious catalytic ability on glucose oxidation reaction. Subsequently, they gave a reasonable explanation for the phenomenon in 2006 through a series of exploration.331 On the basis of the promoting effect of alkali as well as the generation of H2O2, the mechanism of molecular activation for gold catalysis was proposed in Figure 2. As the figure displayed, the interaction of hydrated glucose anion with gold surface atoms could form electron-rich gold species, activating molecular oxygen by nucleophilic attack efficiently. The Au+-O2− or Au2+-O22− couples of the dioxogold intermediate could serve as the bridge to transform electrons from glucose to dioxygen. In this way, the reaction products were formed finally. In addition, Li and co-workers used plasmonic imaging technology to monitor the AuNPs-catalyzed glucose oxidation reaction.332 In their system, 50 nm AuNPs (L-AuNPs) and 13 G


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Figure 3. Proposed mechanism of sulfite oxidase activity of MoO3 nanoparticles. Reprinted from ref 37. Copyright 2014 American Chemical Society.

Figure 2. Catalytic mechanism of Au nanoparticles as glucose oxidase mimics. Reprinted with permission from ref 331. Copyright 2006 Wiley-VCH.

MoIV was reoxidized to initial valence state by the electron acceptor K3[Fe(CN)6].

nm AuNPs (S-AuNPs) were synthesized and then connected by DNA to form gold nanoholo. DNA could control the distance between 50 nm AuNPs and 13 nm AuNPs as well as modulate the catalytic activity of gold nanozymes. Through finite-difference time-domain (FDTD) simulations, they found that a small change in the permittivity of S-AuNPs would influence L-AuNPs with an obvious change of plasmonic resonance. This performance provided a potential to monitor the oxidation reaction of glucose and O2 occurring on SAuNPs. The local surface plasmon resonance spectrum of the gold nanozyme was then monitored. When adding glucose into the solution, an immediate red-shift (2.52 nm) was monitored, which might be the result of the adsorption of glucose on SNPs. After that, a fast blue-shift (6.88 nm) and a slow red-shift (3.53 nm) were measured 2 and 40 min later, respectively. These spectral changes were closely related to the charging and discharging of S-NPs, respectively. Through a series of experiments, they made a hypothesis that the dissolved oxygen in the initial system could be consumed by glucose quickly. Then, oxygen in the air was redissolved to the reaction solution. During this process, it would diffuse to the surface of S-AuNPs to accept the excess of stored electrons, inducing the retarded discharging process of S-AuNPs. 3.1.2. Sulfite Oxidase. Sulfite oxidase (SuOx), one molybdenum-containing enzyme located on mitochondria, can catalyze the oxidation of toxic sulfite to sulfate with cytochrome c as the electron acceptor.333,334 SuOx is important in intracellular detoxification processes while its deficiency may lead to some diseases.335−337 In 2014, Tremel and colleagues demonstrated that molybdenum trioxide (MoO3) nanoparticles possessed an intrinsic SuOx-like activity under physiological conditions which might serve as a potential therapeutic for sulfite oxidase deficiency.37 In their work, potassium hexacyanoferrate (III) (K3[Fe(CN)6]) was chosen as the electron acceptor to rule out the possible side reactions when using cytochrome c. The Km value of 0.59 ± 0.02 mM for sulfite was obtained with a Hill coefficient n (cooperativity constant) of 2.35 ± 0.15 through a Hill equation,338 indicating positive cooperative behavior. The Vmax value and turnover frequency (kcat) of sulfite oxidation was 35.23 ± 1.13 μM min−1 and 2.78 ± 0.09 s−1, respectively. These kinetic parameters of MoO3 nanoparticles were on the same order of magnitude with those of natural SuOx. The possible catalytic mechanism of MoO3 nanoparticles was shown in Figure 3. As the scheme displayed, SO32− first bonded with MoO3 nanoparticles and then was oxidized to SO42− with the reduction from MoVI to MoIV. Through two one-electron steps,

3.2. Peroxidase Family

3.2.1. Peroxidase. Until now, numerous carbon-based nanomaterials have been found to exhibit excellent peroxidaselike properties.339−341 However, their catalytic mechanism is seldom studied. Recently, Qu et al. took graphene quantum dots (GQDs) as the example to explore the catalytic mechanism.342 Combined with experimental data as well as theoretical calculation, they found that the −CO and −O CO− groups could serve as the catalytic activity site and substrate-binding site, respectively. The modification of these groups might effectively improve the catalytic activity of GQDs. On the contrary, the presence of the −C−OH groups would inhibit their catalytic property. Gao, Zhao, and colleagues further investigated the nature of nanocarbon oxides with peroxidase-like property.343 In their study, density functional theory (DFT) as well as molecularlevel insights were carried out. A radical mechanism demonstrated that the large aromatic domains played a significant role for nanocarbon oxides as peroxidase mimics and the carboxyl groups could serve as the active sites for the catalytic reaction of H2O2 to •OH. This work might improve the development of nanocarbon oxide-based peroxidase mimics. Yang, Perrett, and co-workers surprisingly found that Fe3O4 nanoparticles could serve as peroxidase mimics to catalyze the oxidation of a series of substrates in 2007.25 In accordance with the steady state kinetic results, the substrate concentration dependent Lineweaver−Burk plots were parallel. These experimental data illustrated that the catalytic mechanism of Fe3O4 nanoparticles might follow a ping-pong reaction mechanism.344 Fe3O4 could combine with the first substrate H2O2 to form intermediate •OH. The generated •OH would then capture one H+ from the hydrogen donor, for example, TMB. Subsequently, by combining electron spin resonance (ESR) measurements with a radical inhibition assay, the possible catalytic mechanism of Fe3O4-based nanomaterials as peroxidase mimics was proposed by Tang et al.345 In their work, ESR was used to monitor the production of intermediate •OH during the catalytic reaction. It was found that Fe3O4 nanoparticles could also generate intermediate •OH, indicating the similarity to peroxidase. Prussian blue (PB) nanoparticle, an iron-based nanomaterial, also possesses an inherent peroxidase-like property. In order to understand its catalytic mechanism, Gu, Zhang, and coworkers carried out exploratory studies (Figure 4).39 Under an acidic environment, H2O2 exhibits strong oxidation abilities H


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Figure 4. (a) The mechanisms of PB nanoparticles with multienzyme-like properties and (b) relevant reactions in the H2O2-TMB system. Reprinted from ref 39. Copyright 2016 American Chemical Society.

(reaction 1, Figure 4b). In this condition, PB can be oxidized to Berlin green (BG) or Prussian yellow (PY) more easily (reaction 2 and 3, Figure 4b). As Figure 4a demonstrates, the potential of PY/BG is 1.4 V and is between the potential of TMBOx/TMBRe (1.13 V) and H2O2/H2O (1.776 V). Therefore, electrons can be successfully transformed from TMB to H2O2 by PY/BG. Through these processes, TMB is oxidized by H2O2 to produce oxidized TMB (reaction 4, Figure 4b). 3.2.2. Glutathione Peroxidase. GPx is a kind of antioxidant enzyme with selenium-cysteine as its catalytic center.346−350 Inspired by this, Qu, Ren, and co-workers rationally fabricated a novel nanozyme with remarkable GPxlike antioxidative capacity for cytoprotection by assembling GO and selenium.287 Similar to natural glutathione peroxidase, GO-Se nanozyme might follow a ping-pong reaction mechanism to catalyze the decomposition of H2O2: one molecule H2O2 first reacted with nanoselenium to generate selenium oxide intermediate. The obtained intermediate then oxidized GSH to produce GSSG while the selenium intermediate would return to its initial state. With the assistance of glutathione reductase (GR) as well as its coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), GSSG was reduced to GSH. Then the nanoselenium component could react with another H2O2 molecule. Mugesh, D’Silva, and co-workers demonstrated that V2O5 nanowires possessed remarkable GPx-like antioxidant activity which could catalyze the decomposition of H2O2 with the assistance of GSH under physiological conditions.33 The investigation of the mechanism indicated that the surface of V2O5 nanowires could be used as templates for GSH to reduce H2O2 (Figure 5). First, GS− could generate an unstable sulfenate-bound intermediate 2 through the nucleophilic attack of complex 1 on the peroxide bond. This intermediate could then hydrolyze to produce glutathione sulfenic acid 3 and dihydroxo intermediate 4. After that, intermediate 4 would

Figure 5. Proposed glutathione peroxidase mechanism for V2O5 nanowires. Reprinted with permission from ref 33. Copyright 2014 Nature Publishing Group.

react with H2O2 to regenerate complex 1. This catalytic mechanism was like natural GPx. V2O5 nanowires showed typical Michaelis−Menten behavior toward both H2O2 and GSH, with Km values of around 0.11 mM for H2O2 and 2.22 mM for GSH, while the Km values of GPx1 enzyme isoform were 0.025 mM and 10 mM for H2O2 and GSH, respectively. I


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groups were successfully bound together via a weak two-center three-electron bond. Then, Br− could add to one of the O atoms to form an active intermediate, which was best described as an anionic surface site where one of the OH− anions interacted with a Br• radical (IV-b). This step might present a side reaction with the release of an OH• into solution. However, this process was relatively slow due to the relatively high Gibbs free energy (IV-a). The other unaffected OH− was protonated and returned to a neutral surface site (V). After the dissociation of the HOBr product, cerium ions restored to initial Ce3+ site finally (I). During the biocatalytic process, both Ce3+ and the Ce4+/Ce3+ ratio played important roles.

This difference might be due to the different binding affinity of nanozyme/natural enzyme for corresponding substrates. The Vmax of around 0.43 and 0.83 mM min−1 were for H2O2 and GSH, respectively, and the kcat was 0.065 s−1. 3.2.3. Haloperoxidase. In 2012, Tremel’s group found that V2O5 nanowires could serve as vanadium haloperoxidase mimics for thwarting biofilm formation in marine microenvironment.34 In the presence of H2O2, V2O5 nanowires could catalyze halide ions, such as chloride ions and bromine ions, to produce hypohalous acids. The generated hypohalous acids would induce oxidative damage on marine microorganisms, protecting the ships against bacterial adhesion in the ocean. Kinetics analysis indicated that V2O5 nanowires showed typical Michaelis−Menten behavior toward both H2O2 and Br−. And the Km values were 7.3 μM and 0.24 mM for H2O2 and Br−, respectively. Vmax of the reaction was 4.3 × 10−2 M s−1 with a kcat of 8 s−1. These data fitted well with the kinetic parameters of natural vanadium haloperoxidase. By exploring the catalytic mechanism, they found that the exposed lattice planes of V2O5 nanowires had the local vanadium coordination geometry, which was similar to that of the active site of natural vanadium haloperoxidase.29 Therefore, the enzymatic property was dependent on these sites. Due to the high affinity for H2O2, the vanadium atoms could serve as catalytic reactive sites to form intermediate peroxo species. The production of these intermediates was a key step of the enzymatic reaction, which was also important for the catalytic activity of both natural enzyme as well as V2O5 nanozyme. Therefore, the halide ions were able to perform a nucleophilic attack on the more susceptible as well as less electron-rich oxygen atom of the peroxo complex intermediate with the generation of the corresponding hypohalous acid (Figure 6).

3.3. Catalase

Pirmohamed’s group demonstrated that CeO2 nanoparticles could serve as promising catalase candidates in a redox-statedependent manner, and the higher Ce4+ levels would contribute the catalytic ability.351 Ghibelli and co-workers further illustrated the possible catalytic mechanism of CeO2 nanozymes.352 Ce4+ was first reduced by one molecule of H2O2 to form Ce3+, accompanied by the generation of protons and O2. After that, another molecule of H2O2 could combine with the oxygen vacancy site of ⑤ and then oxidize Ce3+ to Ce4+ with the release of H2O (Figure 8). This catalytic process is like natural catalase.101 3.4. Superoxide Dismutase

Up to now, CeO2 nanoparticles have been widely recognized as superoxide dismutase candidates.101,353−355 Different from other trivalent lanthanides, the cerium component can exist in either Ce3+ or Ce4+.356 Due to the presence of Ce3+ and Ce4+ as well as the oxygen vacancies, nanoceria possesses excellent catalytic properties. For the SOD-like property of nanoceria, Ghibelli and colleagues proposed an exhaustive catalytic mechanism.352 In Figure 9, the initial state of nanoceria was noted as ④. As the scheme displayed, superoxide preferentially combined with oxygen vacancy sites around two Ce3+ to form ⑤. An electron was then transferred from one Ce3+ to an oxygen atom to form an electronegative oxygen atom. Therefore, two of the obtained electronegative oxygen atoms could combine with two protons to generate one molecule of H2O2 as well as the intermediate ⑥. The remaining oxygen vacancy site was used to bind another superoxide molecule, leading to the formation of ⑦. After this step, another molecule of H2O2 was generated with the conversion of Ce3+ to Ce4+ ①. The oxygen vacancy site on the surface of ① would lead to the binding of Ce4+ with one molecule of H2O2. In this way, intermediate ② was obtained. ② was not stable which could release two protons with the transformation of two Ce4+ into two Ce3+ to generate intermediate ③. Finally, ③ was converted to initial state ④, and oxygen was released from this step. The ratio of Ce3+/Ce4+ on the surface of nanoceria was significant for the catalytic property and higher ratio could enhance the SOD-like property of nanoceria.101

Figure 6. Biocatalytic mechanism of V2O5 nanowires as haloperoxidase mimics. Reprinted with permission from ref 34. Copyright 2012 Nature Publishing Group.

Subsequently, Tremel and colleagues further found that CeO2−x nanorods could also mimic haloperoxidase for combating biofouling.292 By combining experimental data with theoretical calculations, they proposed a reasonable catalytic bromination mechanism of the CeO2−x nanozymes (Figure 7). In the reaction process, the (110) facet of CeO2−x nanorods was exposed preferentially. On this lattice plane, the H2O could be exchanged against H2O2 (II) and the Gibbs free energy change was close to zero. This exchange was fully irreversible for a (partial) dissociation of H2O2, inducing an oxidation of the Ce3+ site with OH− and OH• (III). The two

3.5. Others

For the catalytic mechanism of metal nanomaterials, Gao and co-workers carried out a series of studies.81,357 On the basis of DFT calculations and experimental data, they demonstrated that the oxidase-like activities of the metals, for example, Au, Ag, Pt, and Pd, could depend on the simple reactiondissociation of O2 supported on the surfaces of these nanomaterials. For SOD-like capacities, the catalytic mechanisms were mainly due to the protonation of O2•− as well as J


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Figure 7. Mechanism of haloperoxidase activity of the CeO2−x nanorods. Reprinted with permission from ref 292. Copyright 2017 Wiley-VCH.

Figure 8. Proposed mechanism of CeO2 nanoparticles as catalase mimics. Reprinted with permission from ref 352. Copyright 2011 Royal Society of Chemistry.

the adsorption and rearrangement of HO2• on their surfaces.81 In addition, they also studied the mechanisms of peroxidaseand catalase-like activities of metal nanomaterials.357 They believed that the enzymatic activities were the inherent properties of these metal nanomaterials. For their peroxidaselike property presented in the acidic condition, it was mainly due to the baselike decompositions of H2O2 on their surfaces. While the catalase-like activity exhibited under neutral or basic conditions were attributed to the acidlike decompositions of H2O2 on their surfaces. The preadsorbed OH groups could only be favorably formed under basic conditions, inducing the transformation of activities between peroxidase and catalase. These studies provide us a thorough understanding of the role of nanozymes in catalytic processes and may lead to new approaches for the improvement of catalytic activities of nanozymes.

4. TUNING THE CATALYTIC ACTIVITIES OF NANOZYMES Similar to natural enzymes, the activities of nanozymes can be tuned by many factors, such as pH,171,358 temperature,25 surrounding environment,359 and metal ions.360−362 In this part, several important factors have been summarized and discussed. For example, the steric effect induced by light can block the contact between nanozymes and their corresponding substrates, leading to the decrease of catalytic activities.44,293 What is more, light induced-pH changes as well as temperature changes can also influence the catalytic performance of nanozymes.363 In addition to the effects of light irradiation, we also explore the influences of size,63,364 morphology,67,365 composition, surface modification groups, substrate selectivity, pH, temperature, as well as the ions or molecules in the reaction systems on nanozymes’ activities. K


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Figure 9. Proposed mechanism of CeO2 nanoparticles as superoxide dismutase mimics. Reprinted with permission from ref 352. Copyright 2011 Royal Society of Chemistry.

Figure 10. Different morphology of Pd nanocrystals with enzyme-like property for cytoprotection. Reprinted from ref 67. Copyright 2016 American Chemical Society.

4.1. Size

4.2. Morphology

It is well-known that the catalytic performance of nanomaterials is related to the size of materials. In 2007, Yang, Perrett, and co-workers studied the catalytic activity of Fe3O4 nanoparticles with different sizes, and 30, 150, and 300 nm Fe3 O 4 nanoparticles were chosen in their work.25 Experimental data demonstrated that 30 nm Fe3O4 NPs possessed the highest peroxidase-like property while 300 nm Fe3O4 NPs displayed the lowest catalytic activity. This might be due to the fact that smaller nanoparticles could have a higher surface-to-volume ratio to combine with corresponding substrates. On the basis of this, we can regulate the catalytic activity of nanozymes by changing their size. For example, Fan et al. proposed that the glucose oxidase-like catalytic activity of AuNPs was sizedependent.63 By comparing the reaction rates of AuNPs with different sizes (13, 20, 30, and 50 nm) under the same conditions, they found that the catalytic performance of AuNPs decreased with the increase of size. In addition, Kang and colleagues proposed a facile method to synthesize Fe3O4carbon nitride hybrid nanocomposite.364 In their system, Fe3O4 nanoparticles were size tunable by controlling the Fe(acac)3 as well as the reaction times. The obtained nanocomposites also exhibited size-dependent peroxidase-like activity when they were used to catalyze the oxidation of TMB in the presence of H2O2.

The biocatalytic performance of nanozyme is also tunable by controlling the shape as well as morphology. To verify this, Yin and Chen’s groups fabricated two Pd nanomaterials: nanocubes and octahedrons.67 By using ESR spectroscopy, they found that Pd octahedrons with lower surface energy possessed higher SOD- and CAT-like properties than those of Pd nanocubes. Further cell experiments illustrated that under the same condition, Pd octahedrons had higher ROS removal ability compared with Pd nanocubes (Figure 10). The theoretical calculation was consistent with the experimental data. This work might promote the development of nanozymes with high catalytic property to combat oxidative stress. In addition, Pathak and co-workers studied the peroxidase-like property of Fe3O4 nanozymes between truncated octahedron and spherical shape.365 Via a series of experiments, they found that truncated octahedron-shaped Fe3O4 nanoparticles exhibited higher catalytic ability compared to spherical-shaped Fe3O4. This might be due to the difference of surface energy facets of two Fe3O4 nanoparticles. 4.3. Surface Modification

In accordance with numerous studies, surface modification, including the thickness of coating, functional group, as well as surface charges can also influence the catalytic abilities of nanozymes.366−368 For example, different functional groups L


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modified AuNPs can exhibit different enzymatic catalytic activities. Citrate-modified AuNPs possess GOx-like property while cysteine-modified AuNPs can serve as peroxidase mimics.72 In 2012, Lin and Chen’s groups explored the difference in the peroxidase-like performance of AuNPs with different surface modifications.366 In their work, “naked”, amino-modified, as well as citrate-modified AuNPs were chosen for comparison. Via a series of experiments, they found that “naked” AuNPs exhibited superior catalytic activity compared to the other AuNPs. When TMB was selected as the substrate, citrate-modified nanozymes exhibited higher peroxidase-like activity than amino-modified AuNPs. This phenomenon was completely reversed when choosing ABTS as the substrate. They gave reasonable explanations for the above results. First, the gold atoms on the surface of AuNPs might contribute to their catalytic activity. Second, the charge characteristics of the surface coating as well as their corresponding substrates might also be crucial to the catalytic reaction. With the addition of surface coatings, the catalytic centers of nanozymes and corresponding substrates may be shielded, leading to a decrease of catalytic efficiency. Perez’s group systematically studied the influence of polymer thickness and the modification group on the surface of nanoceria on oxidase-like property.32 Control experiments indicated that the nanoceria with a thin poly(acrylic acid) coating exhibited higher oxidase-like property than nanoceria with a relatively thicker dextran coating. This might be because the thin poly(acrylic acid) coating was permeable, which would promote the transfer of substrate molecules to and from the nanoceria core surface when compared with a thicker dextran coating. The ultrahigh enzyme catalytic activity of natural enzymes is attributed to its inherent catalytic structure such as catalytic activity center as well as substrate binding site. Inspired by this, a series of studies have been conducted to mimic the structures of natural enzymes to achieve enhanced biocatalytic activities of nanozymes. For example, through the modification of Cu2+ on carbon dots, Willner’s group demonstrated that Cu2+-C dots could serve as horseradish peroxidase mimics since Cu2+ could mimic the catalytic center.166 With the function of βcyclodextrin (β-CD) group on the surface of the Cu2+-C dots (Figure 11a), the obtained β-CD-Cu2+-C dots could exhibit an enhanced peroxidase-like property (Figure 11b). This might be due to the face that β-CD served as the substrate binding site to enrich the substrate. Increasing the specificity for corresponding substrate can also improve the catalytic efficiency of nanozymes. To optimize the peroxidase-like activity of Fe3O4 nanoparticles, Yan, Gao, and colleagues introduced histidine residues onto the surface of the nanoparticles.359 This modification could mimic the natural catalytic microenvironment of peroxidase in which the active site contained a porphyrin ring and histidine residues.367,368 The hydrogen bond formed between the imidazole group of histidine and H2O2369 would increase the affinity of nanozyme to H2O2; therefore, the functionalized Fe3O4 nanoparticles could exhibit enhanced catalytic performance. Qu et al. also discovered that highly efficient graphene-based nanozymes could be constructed by rationally optimizing the amounts of specific surface functional groups.255 In their work, graphene quantum dots were chosen as the nanozyme models. After a facile oxidation reflux approach, the oxygenated groups enriched graphene quantum dots (o-GQDs) were obtained (Figure 12, panels a−c). Due to the abundant carbonyl and

Figure 11. (a) The preparation of β-CD-Cu2+-C dots. (b) The catalytic rates of dopamine oxidation in the presence of (i) β-CDCu2+-C dots or (ii) Cu2+-C dots. Reprinted from ref 166. Copyright 2017 American Chemical Society.

Figure 12. (a) The synthesis of o-GQDs and (b) transmission electron microscopy (TEM) image of o-GQDs. The scale bar was 20 nm. Inset was the corresponding high-resolution TEM image. The scale bar was 5 nm. (c) Atomic force microscopy (AFM) image of oGQDs. The scale bar was 200 nm. Reprinted with permission from ref 255. Copyright 2018 Wiley-VCH.

carboxyl groups, as well as negligible hydroxyl groups on the surface of o-GQDs (Figure 12a), the obtained nanomaterials showed excellent peroxidase-like properties in a broad pH range. The kinetic analysis further illustrated that the Km value of the o-GQDs was five times lower than other GQDs and even an order of magnitude lower than HRP. Furthermore, for bimetallic nanozymes, the tunable enzymatic activity could be achieved by simply verifying the ratio of the metal componment.150 This research may promote the exploration of nanozymes by simple synthesis as well as surface modification. Recently, Liu and colleagues used molecular imprinting technology370 to improve the catalytic activity of nanozymes.371,372 In their work, Fe3O4 nanoparticles were chosen as the nanozyme models. In order to form substrate binding M


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pockets, molecularly imprinted polymers were coated around Fe3O4 nanoparticles.371 The imprinted hydrogels were successfully obtained through the adsorption of substrate molecule, for example, TMB. After removing the TMB template, the resulting cavities could selectively rebind TMB over other substrates such as ABTS. More excitingly, when introducing charged monomers, the catalytic activity of imprinted nanozyme would achieve over 100-fold enhancement compared to that of Fe3O4 nanozyme (Figure 13). This method was also universal for other nanozymes such as nanoceria and AuNPs, which might open up a new strategy for improving the catalytic activities of nanozymes.

Compared with g-C3N4 alone, the obtained Co-g-C3N4 displayed obviously enhanced catalytic performance. Further exploration demonstrated that the peroxidase-like activity of Co-g-C3N4 highly depended on the doping content of cobalt in the nanomaterials. When the doping content was 2.5%, the Cog-C3N4 nanomaterials could achieve the optical catalytic performance. The catalytic mechanism of Co-g-C3N4 nanozymes might be due to the fact that the doping of the cobalt component could efficiently promote the electron transfer of nanozymes from TMB to H2O2, leading to the increase of catalytic property. Similar to this, an effective and general strategy was proposed by Wei’s group to increase the peroxidase-like capacities of carbon-based nanomaterials specifically.376 By doping heteroatom nitrogen into reduced graphene oxide (rGO) and mesoporous carbon (MC), the obtained nanozymes could achieve over 100- and 60-fold higher catalytic activities compared with undoped nanomaterials, respectively. In addition, no obvious influence was obtained on the oxidase-, superoxide dismutase-, as well as catalase-like activities of rGO and MC after doping nitrogen. In addition, forming bimetallic or multimetallic nanocomposites can also obtain improved performances for biocatalysis reactions.147,150,151,380,381 For example, Wu and Xie’s groups designed three Ag-based hollow/porous bimetallic alloy nanoparticles (AgAu, AgPd, and AgPt) with inherent peroxidase-like activity.150 By varying the composition of bimetallic nanoparticles, the peroxidase-like activity could be regulated effectively. Subsequently, they successfully synthesized PdPt alloy nanodots on the surface of Au nanorods.380 The generated Au@PdPt alloy NR could serve as an oxidase mimic to catalyze the oxidation of TMB or ascorbic acid (AA) in the presence of O2. For the oxidation of AA, involving the Pd component into Pt nanostructure could efficiently promote the reaction performance. With the increasing of the Pd nanocomponent, the catalytic ability of Au@PdPt alloy NR increased obviously. For TMB oxidation, the oxidase-like property of Au@PdPt alloy NR increased gradually when enhancing the ratio of Pd to Pt from 0.2 to 5. Taken together, proper alloying of Pd and Pt provided a feasible strategy to tune the oxidase-like activity of Au@PdPt nanocomposites.

Figure 13. Molecular imprinting technology for improving the catalytic activity of nanozymes. Reprinted from ref 371. Copyright 2017 American Chemical Society.

The specific binding ability with substrates can also be achieved by modifying amino acids or other groups with chiral structure on the surface of nanozymes.373,374 Qu’s group constructed enantioselective nanozymes for catalytic reactions.373 In their work, expanded mesoporous silica (EMSN) was used as the template for assembling gold nanoparticles. With the additional modification of chiral cysteine (Cys), the generated Cys@AuNPs-EMSN nanozyme could preferentially catalyze the corresponding chiral substrate. They chose chiral 3,4-dihydroxy-phenylalanine (DOPA) as the substrate for catalytic reaction. When AuNPs-EMSN was functionalized with D-Cys, the D-Cys@AuNPs-EMSN exhibited preference to L-DOPA. On the contrary, the catalytic efficiency of L-Cys@ AuNPs-EMSN was much higher when the substrate was DDOPA.

4.5. Constructing Hybrid Nanomaterials

Up to now, hybrid nanomaterials have attracted numerous interest due to their well-defined structures, enhanced performances, etc.382,383 Inspired by this, nanozymes may achieve supervising catalytic capacities when forming hybrid nanocomposites. Although Au nanoparticles can serve as promising peroxidase mimics, their catalytic activity is often limited by the surrounding pH.357 In order to achieve high catalytic performance over a broad pH range, Qu and Ren’s groups constructed GO-AuNCs hybrid nanozymes.240 In their system, GO was used as the regulator to modulate the peroxidase-like activity of lysozyme-coated Au nanoclusters (AuNCs). TMB had a structure similar to diamine under a weak base condition, leading to the poor solubility in an aqueous solution. With the unique properties of high surfaceto-volume ratio and strong affinity for hydrophobic molecules, GO384 could be used to efficiently adsorb substrate TMB. This could promote the contact of active sites of AuNCs with corresponding substrates, leading to the increase of peroxidaselike ability of AuNCs. Therefore, the obtained hybrid nanozymes could serve as excellent peroxidase candidates over a broad pH range. Recently, dumbbell-like nanoparticles

4.4. Composition

The catalytic activities of nanozymes can also be regulated by changing the proportion of components in the nanomaterials.375−378 In addition, doping some component into nanozymes has been proved as an efficient method for regulating the activities of nanozymes. For example, inspired by the structure and catalytic mechanism of natural enzymes, Qu, Ren, and co-workers proposed a biomimetic strategy to improve the catalytic capacity of nanozymes.379 In natural HRP, the iron porphyrin is considered as the catalytic center while the exposed heme edge serves as the substrate binding site. In their work, Fe3+-doped mesoporous carbon nanospheres (Fe3+-MCNs) were designed to mimic the structure and function of natural peroxidase. Since the Fe component could serve as the catalytic center while carboxyl-modified MCNs could be conducive to combine with substrates, the obtained nanozymes exhibited excellent peroxidase-like capacity. Zhao et al. successfully synthesized a series of cobalt-doped graphitic carbon nitride nanomaterials (Co-g-C3N4).266 N


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have attracted much attention.385 Through the interface of the two nanoparticles, they can provide an additional tuning factor to further enhance catalytic activity. On the basis of this, Sun and co-workers fabricated Pt48Pd52-Fe3O4 nanocomposites with dumbbell-like morphology.234 The obtained Pt48Pd52Fe3O4 hybrid nanomaterials possessed higher peroxidase-like activity compared with single PtPd and Fe3O4 nanoparticles. More excitingly, the Pt48Pd52-Fe3O4 hybrid nanozymes exhibited even higher catalytic ability than natural HRP. The biocatalytic performance can be also enhanced by using integrated nanozymes (INAzymes). For this goal, Wei et al. assembled an artificial enzyme (hemin) and a natural enzyme (GOx) into metal−organic framework (MOF) nanostructures.386 Since hemin was close to GOx in a nanoscaled system, the generated GOx/hemin@ZIF-8 could carry out the glucoseH2O2 cascade reactions with reduced diffusion barrier. In this way, the integrated nanozymes would achieve improved catalytic efficiency. This INAzymes could serve as a promising colorimetric nanoprobe to monitor the glucose level in the brain tissue of living rats. By combining the INAzymes with the microfluidic technology, the dynamic changes of glucose in brains of ischemia/reperfusion-treated living rats were monitored in real time. In addition, Qu, Ren, and co-workers used grapheme-mesoporous silica as the template to assemble two artificial enzymes (hemin and gold nanoparticles) into different locations.387 This positional assembly strategy of artificial enzymes could efficiently prevent interference and enhance the catalytic efficiency of the cascade reactions.

Figure 14. Nanozyme-based colorimetric platform for Hg2+ detection. Reprinted with permission from ref 391. Copyright 2011 Royal Society of Chemistry.

When TMB was used as the substrate, S2− would combine with CM-PtNP via Pt−S bond, leading to the decrease of active sites. On the contrary, when ABTS was chosen as the substrate, the catalytic activity of CM-PtNP could be activated with the addition of sulfide ions. This might be due to the reduction of Pt2+ on the surface of nanozyme to Pt0 after the binding of sulfide to CM-PtNP, leading to more active sites. This switching system could be used as a sulfide ion colorimetric sensor. Previous studies have illustrated that nucleoside triphosphates (NTPs) could serve as coenzymes to increase the oxidase-like property of CeO2 nanoparticles.389 This enhancement in catalytic activity was closely dependent on the type of NTPs. CeO2 nanoparticles could mimic oxidase as well as phosphatase;392,393 the increased catalytic performance might be obtained by coupling the oxidative reaction and NTP hydrolysis. When choosing different NTP, the dephosphorylation would lead to different degrees of enhancement of catalytic properties. Although nanozymes possess excellent thermostability, it is still difficult to realize biocatalytic reactions under high temperature. This may be due to the fact that under high temperature, the poor thermal stability of oxidative products such as ABTS•+ will make the biocatalytic reaction work unefficiently.390 To solve this problem, Qu, Ren, and coworkers used ionic liquid as the modulator to catalyze reactions by EMSN-AuNPs under high temperature (Figure 15a). Ionic liquid394,395 is an attractive solvent that can efficiently stabilize the product ABTS•+ efficiently. In addition, with the assistance of ionic liquid, the nanozyme could exhibit enhanced catalytic performance (Figure 15b). This phenomenon might depend on the weak interactions between ionic liquid and product, cations and anions, as well as the greater solvation power. In addition, adenosine triphosphate (ATP)396−398 could also be used as an ideal boosting agent to realize biocatalytic reaction over a broad range of temperature. Compared with ionic liquid, ATP has the advantage of being cheap and commercially available, easily adaptable to other nanozymes, etc.396 These studies may promote the development of efficient regulators to enhance the catalytic performance of nanozymes.

4.6. pH and Temperature

Besides, the surrounding pH can also influence the catalytic properties on nanozymes.388 For example, under acidic condition, AuNPs can be considered as peroxidase candidates while in neutral or alkaline conditions, AuNPs will exhibit CAT- or SOD-like catalytic properties.82,357 In addition, Gu and Zhang’s groups reported that Fe3O4 nanoparticles could serve as peroxidase mimics to catalyze H2O2 to high toxic •OH in acidic pH condition.171 The formed •OH could kill the cancer cells and inhibit the growth of tumor efficiently. However, under neutral physiological environment, Fe3O4 nanozymes would exhibit catalase-like capability to remove harmful H2O2. Similarly, temperature may also have a great effect on the catalytic performances of nanozymes.49 4.7. Ions or Molecules

Previous studies have demonstrated that ions as well as some molecules can serve as modulators to regulate the catalytic properties of nanozymes.360−362,389,390 These ions or molecules can be used to activate or inhibit the activities of nanozymes. For example, Hg2+, Pb2+, and Bi3+ could stimulate the catalytic ability of citrate-capped AuNPs (Figure 14).391 When these metal ions existed, the citrate protectant on the surface of AuNPs could reduce them to corresponding metal0. Due to the high affinity between metal0 and the surface of AuNPs, the reduced metal could adsorb on the surface of nanoparticles, inducing the change of surface properties as well as the peroxidase-like property of AuNPs. On the basis of this, citrate-capped AuNPs could be applied for the colorimetric detection of heavy metal ions such as Pb2+ and Hg2+. Similarly, Guo et al. found that sulfide ions could also influence the peroxidase-like property of β-casein-stabilized Pt nanoparticle (CM-PtNP).361 Experimental data illustrated that when using different reaction substrates, sulfide ions could exhibit different regulation effect on the peroxidase-like activity of CM-PtNP.

4.8. Light

The construction of light-modulated system may also be used as a promising method to regulate the catalytic efficiencies of nanozymes since light exhibits high temporal and spatial precision. For example, Qu and co-workers constructed a novel O


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Figure 15. (a) The preparation of EMSN-AuNPs and (b) using ionic liquid as the modulator to realize high-temperature catalysis. Reprinted from ref 390. Copyright 2013 American Chemical Society.

Figure 16. Light regulates the activity of nanozymes. Reprinted from ref 406. Copyright 2017 American Chemical Society.

product PNP. With the photoresponsive azobenzene group,408 4-(phenylazo)-benzoic acid could switch between trans- and cis-structures reversibly under UV−vis light. In the presence of visible light, 4-(phenylazo)-benzoic acid was transformed to the trans-structure which had high affinity for Au NP 1 and inhibited the combination of substrate with nanozyme. Therefore, the catalytic activity of Au NP 1 would decrease. Since the TACN·Zn2+ monolayer on the nanozyme was hydrophobic, under UV light, 4-(phenylazo)-benzoic acid was transformed to the cis-structure which had lower affinity due to the increase in polarity of azobenzene. Therefore, by measuring the fluorescence intensity of the product, the catalytic capacity of Au NP 1 could be monitored efficiently. Although different forms of AuNPs can catalyze a variety of biochemical reactions, nanozymes often suffer from the problem of lacking an artificial “switch” that can regulate the catalytic capacity reversibly. In order to realize the real-time control of nanozyme activity, Qu’s group used catalase mimics as an example to design a smart light control system.293 Since catalase can catalyze H2O2 to generate H2O and O2,

nanozyme by modifying chiral metallo-supramolecular compounds ([Fe2L3]4+)399−401 on the surface of carboxylfunctioned graphene oxide nanosheets (GO−COOH).402 With the assistance of a chiral component and the peroxidase-like property of graphene oxide component, this functional system could achieve the intracellular detection of H2O2 in PC12 cells. In addition, this nanozyme possessed excellent enantioselectivity to discriminate between L-dopa and D-dopa. What’s more, experimental data demonstrated that the [Fe2L3]4+-GO-COOH nanozyme was temperaturedependent. Due to the high photothermal conversion efficiency of graphene oxide nanosheets in near-infrared (NIR) region,403−405 the catalytic activity of nanozyme could increase remarkably under the NIR irradiation. Recently, the Prins group used a light-sensitive molecule to control the catalytic activity of nanozymes (Figure 16).406 In their system, 1,4,7-triazacyclononane (TACN)·Zn2+ group modified AuNPs (Au NP 1)407 were used as the nanozyme models. Au NP 1 could efficiently catalyze 2-hydroxypropyl-4nitrophenylphosphate (HPNPP) to form the fluorescent P


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Figure 17. (a) The design of photoresponsive bioorthogonal nanocatalysts; (b) light regulates the activity of nanocatalysts; and (c) intracellular bioorthogonal catalysis. Reprinted with permission from ref 44. Copyright 2018 Nature Publishing Group.

respectively. Generally speaking, the catalytic activities of nanozymes can be well-regulated in many ways, and some studies have shown that the catalytic performance of designed nanozymes is even comparable to that of their corresponding natural enzymes. These studies provide the possibility for the application of nanozymes in practical applications.

intracellular ROS levels can be controlled by reversible regulation of the CAT-like activity of nanozyme. In their work, mesoporous silica (MSN) was used as templates for insitu growth of AuNPs in their channels. Subsequently, azobenzene (Azo) and cyclodextrin (CD) were further modified in the mesoporous silica channels. The obtained nanoparticles were noted as Au_Si_ACD. Given that Azo can produce cis−trans formation change under UV or visible light, therefore, under lighting conditions, the catalytic activity of the AuNPs could be reversible due to the steric effect. By changing the light irradiation, the system could be used to regulate intracellular ROS level, thus changing the viability of cells. Recently, Qu’s group successfully constructed a functional photoregulated nanocomposite for bioorthogonal catalysis.409,410 In their work, palladium nanoparticles were used as transition metal catalyst models.44 Pd nanoparticles were first imbedded into macroporous silica nanoparticles to form silicaPd0. The silica-Pd0 was then modified with azobenzene and βcyclodextrin (Figure 17a). Through light-induced structural changes, the catalytic activity of nanozymes could be modulated efficiently (Figure 17b). This phenomenon could mimic the allosteric regulation mechanism of natural enzymes in living systems.411,412 This light-induced regulation system could achieve the real-time control of bioorthogonal reactions (Figure 17c). Further experimental data illustrated that the photoregulated nanocomposite could successfully catalyze the generation of fluorescent probe rhodamine 110 as well as anticancer drug 5-FU for cell imaging and cancer therapy,

5. RECENT RESEARCH PROCESS OF NANOZYMES 5.1. Nanozymes in Sensing

Colorimetric,413−415 fluorescence as well as electrochemical detection, traditional strategies for quantifying the measured components through corresponding signal change of the reaction system, have been widely used to detect biomolecules. Among them, enzyme-linked immunosorbent assay (ELISA), a traditional colorimetric detection method, has been applied to determine the target with extremely low content in the actual sample.416−418 Through the enzymatic catalytic reaction, this system can achieve immunity detection of the target. Due to their unique enzymatic catalytic properties, nanozymes have received much attention in recent years. Nanozymes, such as peroxidase mimics, can catalyze a colored reaction.25 On the basis of that, nanozyme-based novel biosensors have been successfully designed to detect ions, small molecules, nucleic acids, proteins, etc. 5.1.1. Detection of Ions. Metal ions, especially heavy metal ions, can enter human bodies through numerous ways, such as drinking water, food, and so on.419−,421 These ions are Q


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F− can adsorb strongly on nanoceria since cerium can serve as a hard Lewis acid.436 F− could not only regulate the surface charge of the nanoceria but also accelerate the electron transfer. Therefore, it would improve the catalytic activity of CeO2 nanoparticles. Compared with CeO2 nanoparticles alone, the addition of F− could enhance the catalytic activity over 100-fold. Furthermore, the F−-CeO2 nanoparticles retained an efficient turnover for a long time while CeO2 nanoparticles alone were quickly deactivated within 1 min. On the basis of this property, CeO2 nanoparticles were used for the colorimetric detection of F− in actual toothpaste samples with high selectivity (Figure 18).

not easily metabolized and their accumulation in some organs may lead to chronic poisoning, endangering our health. Therefore, it is of great importance to measure the concentrations of heavy metal ions accurately in our daily food and drinking water. Due to the excellent peroxidase-like property of histidine-modified gold nanoclusters (HisAuNCs), Guo et al. successfully proposed a facile method to selectively detect Cu2+.422 Previous studies had demonstrated that the histidine on the surface of AuNCs could promote the binding of substrates and nanozymes, which would further increase the catalytic activity of AuNCs. Due to the high affinity between Cu2+ and histidine, the peroxidase-like activity of His-AuNCs would be decreased in the presence of Cu2+. Since His-AuNCs could catalyze H2O2 and organic substrate such as TMB or ABTS to form a colored product, Cu2+ could be successfully detected with high selectivity and sensitivity by measuring the changes of absorption signal. In addition, nanozymes can also be used for the detection of Ag+.423 Due to the antibacterial properties, Ag-containing salts or compounds are often applied for disinfection of drinking water and the production of medical products.424−426 However, there are up to 2500 tons of Ag from industrial wastes and emissions annually. Among them, about 80 tons of Ag will be discharged into surface water. It is well-known that Ag+ can be associated with the amine, imidazole, carboxylic acid ester, and thiol groups of proteins, leading to the biotoxicity.427 Therefore, detection of Ag+ in practical drinking water samples is highly important. Recently, Tang and coworkers designed a novel strategy for colorimetric detection of Ag+.423 In their system, bovine serum albumin-stabilized gold nanoclusters were used as peroxidase mimics to catalyze the reaction of H2O2 and TMB. Upon adding Ag+ in the system, the catalytic activity of nanozymes would be strongly inhibited. Further studies demonstrated that Ag+ could react with Au0 on the surface of nanozymes to form Ag0 via redox reaction, leading to the generation of Au@AgNCs. The obtained nanocomposites had a weaker affinity to their corresponding substrates, leading to the lower catalytic performance. Inspired by this phenomenon, the nanozyme-based system could serve as a promising biosensor for Ag+ detection with a detection limit of 0.204 μM. This colorimetric platform could also be used to analyze the content of Ag+ in actual water samples. Furthermore, nanozymes can also be used to detect nonmetal ions. Cyanide ion (CN−),428−430 a deadly poison to human beings, has a strong binding ability to cytochrome c oxidase.431 It may lead to the paralysis of cellular respiration or even trigger severe damage to the central nervous system.432 Therefore, it is of great significance to detect CN− in real samples with high sensitivity. Recently, Huang and Chang’s groups constructed cobalt hydroxide/oxide-modified graphene oxide (CoOxH-GO) nanosheets for the colorimetric detection of CN−.433 CoOxH-GO could serve as a peroxidase mimic to catalyze the oxidation of Amplex Red (AR) in the presence of H2O2. When coupled with glucose oxidase, the system could be used for the detection of glucose. However, CN− could bind with CoOxH-GO to form a Co(II)-cyanide complex, which inhibited the electron transfer between nanozymes and corresponding substrates. Therefore, the catalytic activity of the CoOxH-GO nanozymes would decrease in the presence of CN−. This nanozyme-based system could be used as a biosensor for the detection of CN− in water samples. It is well-known that F− plays an important role in biological, medical, and environmental fields.434,435 As a hard Lewis base,

Figure 18. CeO2 nanozymes for the detection of F−. Reprinted with permission from ref 436. Copyright 2016 Royal Society of Chemistry.

5.1.2. Detection of Molecules. The detection of H2O2 is critical in the fields of food industry, biochemistry, medicine, and environmental protection.437,438 Traditional optical detection method is mainly an HRP-based colorimetric detection assay. Although HRP has the advantages of outstanding catalytic activity and selectivity, the inherent shortcomings highly limit its potential applications. To this end, nanozyme-based colorimetric detection strategy has received much attention. In 2010, Qu and co-workers successfully prepared GO-COOH.239 The obtained nanosheets exhibited excellent peroxidase-like properties to catalyze H2O2 and TMB to produce a blue product. The GO-COOH/TMB system could be used to detect H2O2 with high sensitivity. When combined with GOx, this system could also be applied for selectively detecting glucose in real samples. Nanozymes can achieve the detection of glucose when combining glucose oxidase by using their peroxidase-like ability.439,440 It is well-known that glucose is an important chemical which can affect the nervous system.441−443 This is due to the fact that glucose participates in numerous physiological and pathological cerebral functions, for example, learning and memory, and is related to brain ischemia. Therefore, it is important to monitor the glucose level in brain tissue. Recently, by using metal−organic framework (MIL-101) as the template, Wei, Zhou, and co-workers successfully constructed AuNPs@MIL-101@oxidases nanozymes.62 Upon assembling glucose oxidase, the obtained nanocomposites could catalyze glucose to produce gluconic acid and H2O2. The generated H2O2 could then oxidize leucomalachite green (Raman-inactive reporter) into the active malachite green (MG) with the presence of Au nanocomponents. Since MG exhibited high Raman signals, AuNPs@MIL-101@GOx nanozymes could be used for in vitro detection of glucose in living brains by monitoring the changes of Raman signals (Figure 19). R


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Figure 19. Surface-enhanced Raman scattering coupled with AuNPs@MIL-101@oxidases nanozymes for monitoring glucose and lactate in living system. Reprinted from ref 62. Copyright 2017 American Chemical Society.

As an endogenous biological thiol, GSH participates in many important life processes, such as redox balance, signal transmission, as well as gene regulation.444−446 The abnormal expression of GSH may lead to a series of diseases, for example, inflammation, cancer, or cardiovascular diseases. In order to detect the GSH level efficiently, Dyson and coworkers constructed a colorimetric system based on the unique property of nanozymes.105 In their work, MnO2 nanosheets were chosen as the peroxidase mimics to verify their hypothesis. MnO2 nanozymes could catalyze H2O2 and TMB to produce oxTMB with a color shift from colorless to blue. GSH has a strong reduction capacity that can decompose MnO2 nanosheets and reduce oxTMB, leading to the decrease of absorbance at 650 nm. Therefore, by monitoring the absorbance change at 650 nm, GSH could be detected successfully. In addition to the above-mentioned molecules, nanozymes can also be used to detect other molecules such as dopamine,447 urea,448 ascorbic acid,252 carredilol,100 phosphates,449 heparin,450 etc. 5.1.3. Detection of Nucleic Acids. In the human genome, single-nucleotide polymorphisms (SNPs) are the most common and stable inherited types of sequence variations.451 Previous studies have revealed that SNPs are closely related to the formation and deterioration of tumors. Therefore, the analysis of SNPs can provide an important tool for early diagnosis and risk assessment of malignant tumors. It is wellknown that AuNPs possess GOx-like property.452 AuNPs have a high affinity to single-stranded DNA (ss-DNA) through the gold-sulfur bond.453 The assembling of DNA on AuNPs can change the surface property of AuNPs which limits their GOxlike catalytic ability. Compared with ss-DNA, the binding capacity between double-stranded DNA (ds-DNA) and AuNPs is relatively weak. In the presence of ds-DNA, AuNPs can still retain high enzymatic activity to catalyze the oxidation of glucose. With the assistance of HRP, the obtained H2O2 can oxidize corresponding substrates to transform colored products. Combining the enzymatic capacity and the affinity between ss-DNA and ds-DNA of AuNPs, Fan, Li, and co-workers developed a novel nanoplasmonic probe to detect DNA hybridization (Figure 20).31 Similarly, since graphene also exhibits different affinities to ss-DNA and ds-DNA, therefore, graphene can be used to efficiently distinguish ss-DNA and ds-DNA. Inspired by this property, Dong’s group designed and synthesized hemingraphene hybrid nanosheets through π−π interaction.454 Since

Figure 20. Nanozyme-based nanoplasmonic probe for the detection of DNA hybridization. Reprinted with permission from ref 31. Copyright 2011 Wiley-VCH.

the hemin component possessed unique peroxidase-like ability,249 the obtained hybrid nanosheets could achieve label-free colorimetric detection of SNPs by combining the properties of hemin and graphene. In addition, by in situ growing of “naked” AuNPs on graphene nanosheets, Quan and co-workers engineered a novel hybrid nanozyme to achieve the colorimetric detection of different targets such as sequencespecific nucleic acids, protein aptamers, etc.455 5.1.4. Detection of Proteins. It is well-known that ELISA is one of the most important applications of HRP.456 Therefore, Fe3O4 nanoparticles could serve as promising HRP mimics for the immunodetection of antigens, antibodies, etc. Compared with traditional ELISA, this Fe3O4-based immunoassay was much easier, faster, economic and sensitive. Inspired by this work, researchers also successfully used Fe3O4 nanoparticles to detect carcino-embryonic antigen. Acetylcholinesterase (AChE) can also be detected by nanozyme-based colorimetric sensing platform.107 As we all know, AChE plays an important role in biological nerve conduction.457−460 The disfunction of AChE may lead to some neurological diseases, such as Alzeimer’s disease (AD) and Parkinson’s disease (PD).461−463 To quantitatively detect AChE activity, Lin and colleagues designed a novel colorimetric sensing platform based on the inherent peroxidase-like property of MnO2 nanosheets (Figure 21).107 MnO2 could catalyze TMB to form oxTMB with an obvious absorbance at 650 nm in the presence of H2O2.464 AChE could catalyze the hydrolysis of acetylthiocholine to generate thiocholine.465 The obtained product was able to decompose MnO2 nanosheets, leading to the decreased catalytic performance of MnO2 nanozymes. On the basis of this phenomenon, S


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Figure 21. MnO2-based colorimetric probe for the detection of AChE activity as well as its corresponding inhibitor. Reprinted with permission from ref 107. Copyright 2017 Royal Society of Chemistry.

5.1.5. Detection of Cancer Cells. In addition to the above-mentioned, nanozymes can also be used for the detection of cancer cells.467,468 For example, Perez and coworkers found that under acidic conditions, CeO2 nanoparticles exhibited oxidase-like property to catalyze the oxidation reaction of many organic substrates.32 Taking advantage of the unique capacity, they designed folateconjugated CeO2 nanoparticles for the immunodetection of cancer cells. In their work, folate could selectively recognize folate receptor-overexpressed cancer cells. Combining the CeO2/TMB system, this folate-conjugated CeO2 nanoparticle could achieve the colorimetric detection of cancer cells. Compared with traditional ELISA, the CeO2-based immunoassay exhibited several advantages. First, traditional methods often need the assistance of antibodies which may have the shortcomings such as poor stability. Once the antibodies are denatured, they cannot bind to their corresponding receptors on the surface of cancer cells effectively. Second, compared with CeO2 nanoparticles, HRP has disadvantages such as high cost, poor stability, and durability. Therefore, when HRP is denatured, it may lose its initial catalytic activity. Third, traditional methods need the assistance of H2O2 which is also unstable upon prolonged storage. During the storage process, H2O2 is easy to decompose and will lose its oxidation capacity. However, some researchers think that CeO2 nanoparticles cannot be termed as oxidase mimics, as they might just serve as oxidants during the reaction processing. Despite these arguments, CeO2 nanomaterials, serving as oxidation catalysts, have been widely used in many fields. Inspired by Perez’s work, Qu and Ren’s groups made a further exploration. In their work, folic acid conjugated graphene oxide-gold nanoclusters (FA-GO-AuNCs) nanoprobes were prepared for the colorimetric detection of cancer cells.240 In their system, GO served as the template and lysozyme-stabilized AuNCs could adsorb on the surface of GO via electrostatic interaction. The obtained GO-AuNCs exhibited excellent peroxidase-like property within a broad pH range, especially under neutral conditions. After modifying FA on the surface of GO-AuNCs, the FA-GO-AuNCs nanocomposites could efficiently detect cancer cells. Since cancer cells can overexpress folate receptors on their surface, this biosensor could effectively distinguish cancer cells from normal cells. In a later study, Zhao and colleagues constructed a novel nanocomposite by in situ growth of AuNPs on the surface of periodic mesoporous silica-modified reduced graphene oxide (RGO-PMS-AuNPs).469 The obtained nanocomposites could mimic peroxidase. After the conjugation of FA, the formed RGO-PMS-FA could be used as a promising bioprobe for

AChE activity could be measured by monitoring the absorbance changes of oxTMB. In addition, Gao and co-workers designed a peptideconjugated gold nanoprobe for the immunodetection of integrin GPIIb/IIIa on humanerythroleukemia cell line (HEL, Figure 22).466 Through the bioconjugation method,

Figure 22. Peptide-conjugated gold nanoprobe for the immunodetection of integrin GPIIb/IIIa. Reprinted from ref 466. Copyright 2015 American Chemical Society.

this peptide-AuNPs probe could selectively recognize the integrin on the surface of cytomembrane. Since AuNPs possessed peroxidase-like property, by combining H2O2 and TMB, this system could quantitatively count the expression level of integrin on HEL in an amplified immunoassay. Furthermore, with the unique nonlinear optical property of AuNPs, the protein on cell membrane could be directly visualized through two-photon photoluminescence. Recently, Xia’s group successfully constructed Pd nanocubes as the cores and then coated with a thin layer of Ir on the surface.147 The generated Pd−Ir core−shell nanocubes exhibited significantly enhanced peroxidase-like catalytic ability. Compared with Pd, Ir is more reactive for adsorbing oxygen-containing species. Therefore, once depositing Ir layer on Pd nanocubes, the surface reactivity of Pd could be enhanced efficiently. With the steady-state kinetic assays, the catalytic constants of Pd−Ir nanocubes were about 20-fold and 400-fold higher than those of single Pd nanocubes and natural HRP, respectively. With their excellent catalytic ability, this Pd−Ir core−shell nanocube could serve as a novel biosensor for immunodetection of human prostate surface antigen. Compared with traditional HRP-based ELISA, the Pd−Ir nanocube-linked immunoassay was more sensitive with a ∼110-fold lower detection limit. T


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colorimetric detection of cancer cells with high selectivity and sensitivity (Figure 23). The excellent enzyme-like properties

After that, the use of natural enzymes for wastewater treatment has received increasing attention. Among these enzymes, HRP is the most widely applied enzymes. HRP can catalyze H2O2 to generate highly reactive •OH. The obtained •OH then can oxidize many organic pollutants, such as phenols and aromatic amines to insoluble precipitated products.481 Although natural enzymes possess many advantages, their shortcomings all limit their further applications in environmental treatment. Nanozymes, as the mimics of natural enzymes, have shown potential in the treatment of environmental pollution. Compared with natural HRP, Fe3O4 nanozymes have the advantages such as lower cost, higher stability, and cycling efficiency. Therefore, Fe3O4 nanoparticles may be more suitable for wastewater treatment. Inspired by this, Yan’s group used Fe3O4 nanoparticles as peroxidase mimics to catalyze the degradation of phenols.482 In addition, some researchers also used Fe3O4 nanoparticles for the catalytic decompositions of methyl blues, rhodamine B, and other organic substances.483 Unfortunately, Fe3O4 nanoparticles are easy to aggregate spontaneously due to the high surface energy. This may lead to a significant loss of catalytic activity. What is more, just under a relatively low and narrow pH range, Fe3O4 nanoparticles may have excellent catalytic ability. These all limit their potential applications in wastewater treatment. To solve these problems, Huang et al. designed Fe3O4-MWCNTs hybrid nanocomposites by using multiwalled carbon nanotubes (MWCNTs) as the templates.191 Owning to the large surface area,484,485 MWCNTs could efficiently disperse Fe3O4 components, which highly prevent their aggregation. On the basis of the unique properties of MWCNTs and Fe3O4, the obtained nanocomposites could achieve enhanced peroxidase-like capacity compared with their single component. Fe3O4-MWCNTs could maintain excellent catalytic activity to catalyze the reaction of H2O2 and methylene blue under a wider pH range and achieve removal efficiency over 98.68%. In addition, the Fe3O4-MWCNTs had excellent recycling efficiency which could still retain initial catalytic ability after 5 cycles. In addition, many other nanomaterials with a peroxidase-like property have also been reported to catalyze the degradation of organic pollutants. For example, BSA-Cu3(PO4)2·3H2O hybrid nanoflowers could be used as peroxidase mimics with excellent biocatalytic property, stability, as well as durability.49 In the presence of H2O2, this hybrid nanoflower could catalyze the decomposition of organic pollutants such as rhodamine B with high efficiency, demonstrating their possibility for treating wastewater. Subsequently, Qu and Ren’s groups found Fe3+MCNs nanozymes could serve as potential candidates of HRP for the removal of organic pollutants. Similar to HRP, laccases can also be used in environmental remediation. Since laccases are multicopper oxidases,127 based on this, Liu, Liang, and co-workers assembled guanosine monophosphate (GMP) with copper ions to form a MOF structure.126 The generated Cu/GMP MOF could serve as a laccase mimic to catalyze the oxidation reactions of polyphenol substrates such as phenol, hydroquinone, naphthol, and catechol. These phenolic compounds, as important industrial chemicals, may cause environmental problems. Therefore, the Cu/GMP MOF system with inherent laccase-like activity might have potential in environmental protection. 5.2.2. Nanozymes in Degrading Chemical Warfare Agents. Chemical warfare agents (CWA) are chemical substances which aim at war with great toxicity and mass

Figure 23. Using the peroxidase-like property of RGO-PMS-AuNPs for the detection of cancer cells and cancer therapy. Reprinted from ref 469. Copyright 2015 American Chemical Society.

make nanozymes as powerful probes for detecting numerous substances, including ions, small molecules, nucleic acids, proteins, cancer cells, and so on. Moreover, Yan’s research group has applied nanozymes into ELISA test kits for commercial use, and the nanozyme-based strips can be used for viruses, toxins detection, environmental monitoring, and food safety measurement.51 This practical application of nanozymes may encourage us to develop novel nanozymebased systems for actual biosensing use. 5.2. Nanozymes in Environmental Treatment

With the development of industry, its pollution problems to the surrounding environment followed.470 Environmental pollution is often caused by human factors, such as indiscriminate discharge of industrial wastewater and wastegas. It can change the composition of the surrounding environment, which may disturb and destroy the ecological system and the normal life of human beings.471,472 For example, the minamata disease in Japan was caused by the fact that Showa Denko Company dumped untreated mercury-containing wastewater into the sea.473,474 Up to now, environmental pollution has been a global problem and it has become the consensus that we need to strengthen the environmental protection and management efforts. Since the 20th century, biotechnology, as a cross between chemistry and biology, has become more and more familiar to people. Until now, biotechnology has been widely applied in food processing, biomedicine, agricultural industry, etc.475,476 The applications of biotechnology contribute to solving the problem of environmental pollution. Especially, enzyme and enzyme engineering play a vital effect on the treatment of environmental pollution.477−479 5.2.1. Nanozymes in Degrading Organic Pollutants in Wastewater. Among various pollutants, organic pollution has become one of the important sources of pollution. Traditional physical and chemical methods often need complicated process and expensive equipment. Since the early 1980s, Klibanov and co-workers, for the first time, used peroxidase to catalyze the degradation of phenols and aromatic amines in wastewater.480 U


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destruction.486 Among them, nerve agents,487 a kind of phosphate bond containing CWA, are one of the most toxic chemicals known to human beings. They can enter the body through various ways such as respiratory tract and skin. When combining with cholinesterase, these nerve agents will deactivate the activities of cholinesterase, leading to dysfunction of the nervous system.488 Recent global military events, for example, the military conflicts in Syria, have led to concentrated efforts to look for efficient methods to rapidly destroy these toxic chemicals. Up to now, solutions are mainly focused on personal protection, mass destruction of chemical weapons storage, and controlling the leakage of CWA.489−492 Some solid heterogeneous materials, such as modified activated carbon and metal oxides, provide the potential for destroying the above-mentioned CWA.493 However, these materials often suffer from inherent shortcomings such as poor absorption capacities and ease of deactivation. Therefore, the exploration of novel materials for efficient catalytic degradation of nerve agents and analogues is urgently needed. Recently, Zhang’s group successfully modified an organic group with organphosphorus hydrolase (OPH)-like property on the surface of GO through self-assembly.494 The obtained nanocomposites could serve as OPH mimics for the efficient degradation of paraoxon. Further investigation of the reaction mechanism indicated that this excellent biocatalytic property might be due to the synergistic effect between the presence of imidazole clusters and −COOH groups on the surface of GO and Zn2+. What’s more, Efremenko, Kabanov, and co-workers designed a polyionic nanocomposite through the self-assembly of hexahistidine tagged organphosphorus hydrolase and PEGmodified-poly(L-glutamic acid) diblock copolymer.495 The obtained nano-OPH could not only remain the catalytic activity of OPH but also enhance its stability during the storage process. This nanocomposite was able to catalyze the decomposition of poisonous organophosphorus compounds, such as pesticide, paraoxon, and the warfare agent O-ethyl S(2-diisopropylaminoethyl) methylphosphonothiolate (VX) and protect biological systems from neural damage. Organophosphorus nerve agents, such as paraoxon, parathion, and malathion, can inhibit the activity of acetylcholinesterase, leading to paralysis, respiratory failure, and even death.496−498 In the bacteria system, there is a phosphotriesterase (PTE), which can effectively decompose these organophosphorus nerve agents.499−501 Inspired by this, Mugesh’s group designed vacancy-engineered nanoceria (VE CeO2 NPs) as PET mimics to degrade nerve agents effectively.327 With paraoxon as the model, in the presence of histidine or N-methylmorpholine, VE CeO2 NPs could catalyze the decomposition of paraoxon. Compared with single nanoceria, VE CeO2 NPs possessed better catalytic ability. Due to the vacancies on the surface of nanoceria, dual oxidation states of Ce ions existed in the reaction environment. The catalytic hotspots played important roles in capturing and activating corresponding substrate in the active sites. Further investigation of reaction mechanism demonstrated that the unique chemical property of VE CeO2 NPs mainly resulted from the selective and preferential binding of water and paraoxon with Ce ions in different oxidation states. Besides, the distance between Ce3+ and Ce4+ could also influence the catalytic ability of VE CeO2 NPs. Their work may promote the exploration of novel methods for the treatment of nerve agents as well as broaden the potential applications of nanozymes.

Furthermore, some organic nanomaterials can also be used for the degradation of chemical warfare agents.502−504 For example, Hupp, Farha, and co-workers successfully designed Zr-based MOF, NU-1000, to catalyze the degradation of chemical warfare agents.491 Compared with other MOF materials, NU-1000 had larger channels that could allow phosphate ester molecules to enter the whole structure freely. In NU-1000, Lewis-acidic ZrIV ion could serve as the catalytic activity center to efficiently catalyze the decomposition of nerve agent stimulant dimethyl 4-nitrophenyl phosphate (DMNP). Besides, NU-1000 could also catalyze the degradation of the highly toxic chemical warfare agent Opinacolyl methylphosphonofluoridate (Soman) efficiently. Recently, Jiang et al. designed an integrated nanocomposite by immobilizing natural OPH into a MIL-100(Fe) metal− organic framework.505 The OPH component could efficiently catalyze organophosphate nerve agents into 4-nitrophenol, while the MOF component could further catalyze the hydrogenation of 4-nitrophenol to generate 4-aminophenol with relatively low toxicity. Through this cascade reaction, organophosphate nerve agents could be efficiently transformed to 4-aminophenol and the toxicity decreases dramatically. 5.2.3. Nanozymes in Inhibiting Biofilm Formation. In the ocean environment, microorganisms such as bacteria can adsorb on the surface of hull, propeller, anchor, and other regions of the ships, leading to the formation of marine biofouling (Figure 24b).506 The accumulation of micro-

Figure 24. (a) V2O5 nanowires-based paint layer coated on the surface of metal, (b) bacteria can attack metal layer easily in ocean environment, (c) HOBr generated by V2O5 nanowires in the presence of Br2 and H2O2, and (d) V2O5 nanowires with excellent vanadium haloperoxidase-like property against bacteria. Reprinted with permission from ref 34. Copyright 2012 Nature Publishing Group.

organisms on ships will increase the resistance of water flows, thereby increasing the fuel consumption and greenhouse gas emissions. The marine biofouling507,508 has aroused extensive attention. A feasible solution is to design antifouling coatings to inhibit the adhesion of bacteria. For example, tributyltin-free antifouling coatings, metal complex- or biocidebased paints have been proven to inhibit marine biofouling efficiently.509,510 However, these materials may have problems such as leakage of metal ions (for example, Cu2+ and Zn2+) and the resistance of bacteria, which will induce some damage to the environment. In the ocean system, certain seaweeds can V


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Figure 25. (a) o-CNTs with excellent peroxidase-like activity for antibacteria; photographs of wound healing on the (b) backs of mouse and (c) corresponding wound area at different times under different treatments. The growth condition of bacterial from the wound tissues after (d) different treatments and (e) corresponding bacterial numbers. Asterisks indicate statistically significant differences (*P < 0.05, **P < 0.01, and ***P < 0.001). Reprinted from ref 261. Copyright 2018 American Chemical Society.

possess multienzyme-like catalytic properties.26,101 Inspired by these unique properties, Tremel and co-workers discovered that CeO2−x nanorods possessed inherent haloperoxidase-like activity.292 In the presence of H2O2, CeO2−x nanorods could catalyze the bromination reaction of signaling compounds, leading to the inhibition of bacterial quorum sensing. This regulating ability of bacteria quorum sensing was similar to natural or artificial vanadium haloperoxidases and halogenases. Compared with commonly used cuprous oxide antifouling agent, CeO2−x nanorods had the advantages of low toxicity and excellent catalytic ability. When adding CeO2−x nanorods into paints, they still retained high antifouling capacity to efficiently inhibit the adhesion of microorganisms. Taken together, although nanozymes have great advantages in catalyzing the degradation of organic pollutants, chemical warfare agents, etc., great efforts such as the improvement of catalytic activities are still needed to achieve the practical applications in environmental treatment.

produce vanadium haloperoxidase (V-HPOs) to catalyze the oxidation reaction of halides X− (for example, Cl− or Br−) to generate corresponding hypohalous acids (HOX) with the assistance of H2O2.511,512 HOX have a highly oxidizing property which can suppress the adhesion of bacteria on seaweeds by killing the bacteria or oxidizing the biofilms. Therefore, V-HPOs can be used as additives in antifouling paints. Though promising, like other enzymes, V-HPOs also suffer from inherent shortcomings such as complicated extraction process, high cost, and poor stability. Inspired by this, Tremel and colleagues demonstrated that V2O5 nanowires could serve as V-HPOs mimics to catalyze Br− and H2O2 to produce HOBr.34 The obtained HOBr could efficiently kill both Gram-positive bacteria and Gram-negative bacteria (Figure 24). Compared with International Maritime Organization (IMO)-approved antifouling products, the V2O5 nanowires possessed better biosecurity. When adding this nanowire into commercial paint (Figure 24a), it still remained excellent catalytic activity to inhibit the accumulation of marine microorganisms on the ships (Figure 24, panels b−d). This stable, low toxic, and inexpensive biomimetic material may become a new sustainable environmental protection material used in the antibacteria, antifouling, disinfection, and other fields. Up to now, using biomimetic materials to inhibit the formation of biofilms in ocean environment is a relatively environmentally friendly and cost-effective antifouling technology. Among them, vanadium complexes or V2O5 nanoparticles are the main antifouling materials.34,513−515 Though promising, these vanadium-based compounds may be mutagenic, carcinogenic, and teratogenic. These side effects will largely limit their potential applications. Because of the Ce3+/ Ce4+ redox potential, Ce can switch between the dual oxidation states reversibly.101 Therefore, there are oxygen vacancies in fluorite-type ceria (CeO2−x). With the advantages of unique redox and structural properties, outstanding oxygen diffusion and oxygen storage/release ability, excellent stability, and environmental compatibility, nanoceria have been reported to

5.3. Nanozymes in Antibacteria and Cancer Treatment

5.3.1. Nanozymes in Antibacteria. Until now, bacteriainduced infectious diseases, as one of the greatest health problems around the world, have afflicted millions of people annually.516,517 Traditional antimicrobial agents are mainly antibiotics. In addition, some inorganic agents, such as metalcontaining inorganic salts, natural antibacterial agents, and some organic agents can also be used as antibacterial materials.518−521 However, these antibacterial agents have some drawbacks, for example, inorganic antibacterial agents can easily cause leakage of metal ions, leading to pollution of the surrounding environment. Besides, natural antibacterial agents have shortcomings such as poor antibacterial efficiency and heat resistance. In addition, organic agents often have problems such as complicated preparation processes, high cost, and antibiotic resistance.522 To this end, it is urgent to develop novel, stable, and efficient antibacterial materials to confront bacteria-induced diseases. W


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Figure 26. (a) Preparation of AA@GS@HA-MNPs and (b) AA@GS@HA-MNPs achieve a synergistic antibacterial effect. Reprinted with permission from ref 531. Copyright 2016 Wiley-VCH.

peroxidase-like property that could achieve a broad spectrum of antibacterial effects under a physiological level of H2O2. In addition, this CNA system could also destroy biofilms by decomposing membrane components such as nucleic acids, proteins, and polysaccharides as well as prevent the formation of new biofilms. Furthermore, CNA-based Band-Aids could not only efficiently prohibit bacterial infections but also accelerate wound healing. More importantly, with the excellent peroxidase-like property, CNA could also be applied to alleviate MRSA-induced lung infection. Due to the excellent biocompatibility as well as the high efficiency of near-infrared photothermal conversion, molybdenum disulfide (MoS2) nanomaterials have been used as promising photothermal reagents for cancer therapy.526,527 In addition, MoS2 nanomaterials exhibit inherent peroxidase-like property which can be applied for the colorimetric detection of some molecules such as H2O2 and glucose.528 On the basis of these unique properties, Zhao et al. prepared PEG-modified MoS2 nanoflowers (PEG-MoS2 NFs)222 which exhibited both enzymatic catalytic ability and photothermal conversion efficiency that could achieve synergetic antibacterial effect. Because of the unique peroxidase-like capacity, MoS2 could transform a low level of H2O2 to •OH, avoiding the toxicity induced by high concentration of H2O2. The generated •OH had a strong antibacterial ability which could induce initial oxidative damage to the cell wall and cell membrane, making the bacteria more vulnerable. Combined with the photothermal conversion ability of MoS2, their system could enhance the permeability of damaged membrane, leading to the enhanced sensitivity of bacteria to heat. Therefore, it could shorten the time of the photothermal therapy (PTT) and reduce PTT-induced side effects. Furthermore, the hyperthermia induced by 808 nm irradiation of PEG-MoS2 NFs could accelerate the oxidation of antioxidant GSH, leading to the destruction of the protection system in bacteria. In this way, the antibacterial effect of PEG-MoS2 NFs was further improved. Compared with single catalytic treatment or photothermal therapy, the PEG-MoS2 NFs could achieve a rapid and efficient killing outcome against both Gram-negative and Gram-positive bacteria, promoting wound healing.

In natural environment, peroxidase, as a member of cytochrome P450 family,523 participates in many important living processes. Peroxidase is a metalloprotease in which iron porphyrin serves as the catalytic center.524,525 It can catalyze H2O2 to produce high activity •OH, oxidizing numerous organic substrates. On the basis of that, Qu and co-workers successfully applied GQDs with peroxidase-like property to antibacterial systems.35 Although H2O2 has the inherent bactericidal effect, the needed concentration is relatively high. In the GQD system, GQDs were demonstrated to catalyze the transformation of H2O2 to highly oxidized •OH and killing bacteria efficiently even under relatively low concentration of H2O2. Compared with traditional inorganic and organic antibacterial agents, GQDs exhibited advantages such as low biotoxicity, high stability, and excellent bactericidal effect. What’s more, this GQDs/H2O2 system could achieve excellent antibacterial efficiencies on both Gram-negative and Gram-positive bacteria. In order to further explore the potential of GQDs in practical applications, GQD-Band-Aids were designed for wound disinfection. Experimental results showed that the GQD-Band-Aids could efficiently inhibit the wound disinfection under a low dose of H2O2. Recently, Qu et al. synthesized oxygenated-group-enriched carbon nanotubes (o-CNTs) via a one-pot oxidation reflux.261 The obtained o-CNTs exhibited enhanced peroxidase-like activity for biocatalytic reaction over a broad pH range (Figure 25a). The further exploration of catalytic mechanism indicated that because of the “competitive inhibition” effects among carboxyl, carbonyl, as well as hydroxyl groups, the noncatalytic sites were decreased, leading to the significant enhancement of the catalytic property of o-CNTs. The excellent peroxidase-like property of o-CNTs could be used for antimicrobial application. Experimental results indicated that o-CNTs could serve as powerful peroxidase candidates to catalyze the formation of hydroxyl radical, killing bacteria efficiently and protecting the tissue against edema and inflammation induced by bacteria infections (Figure 25, panels b−e). Further work was also carried out by Qu et al. by using ultrathin graphitic carbon nitride (g-C3N4) as the template for in situ growth of AuNPs.56 The obtained g-C3N4@AuNPs (CNA) nanocomposites exhibited a remarkable enhanced X


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Figure 27. Scheme illustration of nanozyme-based light-controlled antibacterial hydrogel for wound healing. Reprinted from ref 363. Copyright 2017 American Chemical Society.

It is believed that the stimulation to generate toxic •OH is the main mechanism of bactericidal antibiotics.529 However, the lack of targeting to bacteria cells and the difficulty to directly deliver it to the infected sites limit its further application. The sustained generation of •OH on the surface of the bacteria may be a feasible solution for antibacteria. Reports have demonstrated that AA, as a pro-oxidant, could serve as the prodrug of H2O2 to treat drug-resistant infections and cancers.530 Inspired by this unique property, Qu and coworkers successfully constructed an “on-demand” prodrug delivery system for the treatment of bacterial infection.531 In their work, hyaluronic acid modified graphene-mesoporous silica (GS) nanosheets were used as the nanocarriers and AA served as the prodrug of H2O2. Since ferromagnetic nanoparticles (MNPs) possessed a peroxidase-like property, they could catalyze AA to produce •OH. The generated •OH could efficiently destroy the membrane structures of bacteria as well as kill the bacteria. In their system, GS was first combined with AA via electrostatic interaction. After that, hyaluronic aciddopamine complex was modified on the surface of GS. Because of the abundant functional groups, dopamine (DA) on the surface of nanosheets could combine with vancomycinmodified MNPs. The obtained nanocomposites were noted as AA@GS@HA-MNPs (Figure 26a). Vancomycin could target both Gram-negative and Gram-positive bacteria.532 When AA@GS@HA-MNPs reached the infection site, hyaluronidase533 secreted by bacteria could decompose HADA and then release the packaged AA. In this way, MNPs could efficiently transform AA to toxic •OH, destroying the biofilm as well as killing the bacteria. What is more, with the antibacterial effect of vancomycin and the photothermal therapeutic effect of graphene,534 the AA@GS@HA-MNPs could achieve a synergistic antibacterial effect (Figure 26b). As we all known, the wound healing process is mainly divided into two stages: the inflammatory stage and the cell proliferation stage.535,536 Therefore, the ideal tissue healing material should have the ability to kill bacteria in the first phase and then promote wound healing in subsequent phases. However, most of the commercialized Band-Aids are only appropriate for the first stage while they have no or even side effects on the cell proliferation. To this end, Qu’s group prepared a light-controlled antibacterial hydrogel by integrating photothermal nanomaterial GO, photobase reagent malachite green carbinol base (MGCB), and CeO2 nanozyme into the agarose gel (Figure 27).363 The catalytic property of CeO2 nanoparticles was dependent on the surrounding pH value. Under acidic condition, CeO2 nanoparticles exhibited oxidase- and peroxidase-like abilities to catalyze the generation of reactive oxide species, killing the bacteria efficiently. While under neutral or weak alkaline conditions, CeO2 nanoparticles

would serve as catalase and superoxide dismutase mimics to protect cell components against oxidative damage and promote cell proliferation.101 In consideration of the unique property of CeO2 nanoparticles, by adjusting the environment around the wound sections, CeO2 nanoparticles could be used as an ideal adjuvant for wound healing. In their system, GO possessed excellent photothermal conversion ability which could accelerate the generation of free radicals. In addition, MGCB could release OH− after ultraviolet light irradiation.537 Under this condition, the surrounding pH would increase gradually with the generation of OH−. The increased pH could then activate the antioxidative enzymatic capacities of CeO2 nanoparticles, promoting the cell proliferation in wound sections. This GO-MGCB-CeO2-based hydrogel could kill bacteria efficiently as well as promote cell proliferation, leading to the acceleration of wound healing. In addition, nanozymes can also be used to deal with biofilm-associated oral diseases.61 Bacterial biofilms are the bacteria that adhere to the surface of contact, secreting proteins, polysaccharides, and other biomolecules.538,539 These biomolecules will then wrap bacteria, and bacterial aggregates are then formed. Many human infectious diseases result from biofilms. Among them, dental cavities are one of the most common and costly biofilm-associated oral diseases.540 When Streptococcus mutans and other bacteria use the sugar in food to generate the extracellular polysaccharides and concentrate them on the surface of the teeth, the surrounding environment will become more acidic gradually, leading to the formation of cavities biofilm finally.541 Because bacteria can be embedded in the extracellular matrix, it is difficult to remove the oral biofilm. Besides, the acidic environment around the biofilm can dissolve the enamel-apatite component of teeth, resulting in the onset of dental cavities. Given the unique properties of nanozymes, Koo’s group chose Fe3O4 nanoparticles (CATNP) as the peroxidase mimics to inhibit the formation of oral bacterial biofilm.542,543 Under the acidic environment of the oral biofilm, CAT-NP could catalyze the generation of •OH, destroying the biofilm matrix and killing the embedded bacteria. This CAT-NP could also alleviate the mineralization of apatite in the acidic environment and protect the teeth efficiently. Furthermore, the CAT-NP/H2O2 system could effectively inhibit the formation and deterioration of cavities while there were no obvious side effects on oral mucosal tissue. On the basis of this work, they further utilized ferumoxytol nanoparticles to destroy biofilms as well as suppress tooth decay in vivo.544 In their work, a rodental cavities model was constructed. Their results indicated that after topical oral of ferumoxytol and H2O2, the development of dental cavities was inhibited remarkably. This demonstrated that the ferumoxytol Y


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5.3.2. Nanozymes in Cancer Therapy. RNA interference,550−552 mediated by RNA-induced silencing complex (RISC), is a basic mechanism of gene regulation.553 RISC is an endonuclease consisting of multiple protein complex. The RISC can incorporate one strand of a small interfering RNA or microRNA. By using this obtained RNA strand, RISC can recognize and capture a complementary mRNA.554 After that, this captured mRNA will be cleaved into two pieces by RISC. Inspired by the structural and functional properties of the RISC machinery, Cao’s group designed an artificial nanozyme to mimic intracellular RISC machinery to cleave target RNA.555 In their system, the AuNPs could serve as the backbones of the nanozymes, providing large surface areas to modify nonspecific endonucleases and ss-DNA oligonucleotides. The obtained nanocomposites were noted as RNase ADNA-NPs. In this nanozyme, RNase A served as the catalytic center, while ss-DNA could combine with target RNA via base complementary pairs. The combined target RNA was then cleaved by neighboring endoribonuclease. They chose Hepatitis C virus (HCV) as a model to verify the feasibility of their design. Their results demonstrated that the RNase ADNA-NPs could efficiently cleave HCV RNA, silence gene expression, and inhibit virus replication. This nanozyme might have potential in protein expression related diseases such as viral infections and cancers. Nanozymes can also be used in photodynamic therapy (PDT) under hypoxic conditions.65 Metal−organic frameworks (MOFs) are crystalline porous hybrids consisting of metal-based nodes and organic ligands.556 Because of their good biocompatibility, biodegradability, and suitable sizes, nanoscale MOFs have attracted attention in biosensing, biocatalysis, as well as biomedical fields.557 More recently, by converting oxygen from the tumor tissue into reactive singlet oxygen (1O2), photosensitizer-based MOFs have been applied for PDT.558−560 Although promising, the therapeutic effects of PDT are often limited by the hypoxic environment of tumor tissue.561 It is well-known that hypoxia is commonly present in most solid tumors. Because of the uncontrolled proliferation of cancer cells, the oxygen supply will be reduced in tumor tissues. The consumption of O2 as well as the PDT-induced shut down effects of vascular can further aggravate hypoxia which leads to decreased PDT efficiency. Traditional methods for hypoxia are constructing oxygen delivery systems or enzyme-based oxygen generating systems.562−564 However, those methods may suffer from inherent problems such as limited oxygen supply, poor stability, high cost, etc. Since many nanomaterials can serve as catalase mimics to catalyze H2O2 to generate O2,26−30 Qu et al. demonstrated a novel strategy for photodynamic therapy under hypoxic conditions by modifying nanozymes on photosensitizer integrated MOFs.65 In their system, platinum nanoparticles were chosen as catalase mimics for the generation of O2. After assembling platinum nanoparticles on the surface of MOFs, the nanocomposites could increase the generation of 1O2 by catalyzing the decomposition of H2O2 in hypoxia tissue. The nanozyme-based MOFs may serve as efficient nanoagents for cancer therapy under hypoxia. Until now, much effort has been devoted to the development of novel nanozymes, regulation of their catalytic properties, as well as exploration of the potential applications. However, controlling the in vivo catalytic performance of nanozymes in a target cell is still a challenge. To overcome this problem, Gao and Yan’s groups constructed nitrogen-doped porous carbon nanospheres (N-PCNSs) with oxidase-,

nanoparticles might serve as potential therapy agents for biofilm-related oral diseases. Extracellular DNA (eDNA), as an essential structural constituent, participate in the formation of biofilm.545 eDNA can increase the adhesion of initial bacteria on the surface of contact and enhance the aggregation of bacteria.546 Besides, it can efficiently connect these adsorbed bacteria with other extracellular polymeric substances. Finally, the mature networks were formed which kept all components together. In order to inhibit the formation of biofilm as well as disintegrate the preformed biofilm, much effort has been devoted. Among them, the cleavage of eDNA by desoxyribonuclease (DNase) is considered as a promising method.547 Recently, some Lewis acidic metal ions-based biocatalysts have been reported as nuclease mimics for the decomposition of DNA or RNA.548 On the basis of that, Qu and colleagues successfully constructed a DNase-mimetic artificial enzyme (DMAE) for combating bacterial biofilms.323 In their work, Fe3O4/SiO2 core/shell nanoparticles were used as the scaffolds for further modifying AuNPs. After that, CeIV nitrilotriacetic acid complexes,549 as DNase mimics, were covalently conjugated to the surface of AuNPs, and the DMAE was obtained finally (Figure 28a). With the unique DNase-like catalytic ability, the

Figure 28. (a) Preparation of DMAE, (b) DMAE-modified surface could efficiently decompose eDNA and inhibit the formation of biofilm, and (c) DMAE could destruct the preformed biofilms. Reprinted with permission from ref 323. Copyright 2016 Wiley-VCH.

DMAE could efficiently cleave both model substrates and eDNA with better operational stability and higher cycling efficiency. After coating DMAE on the surface of substratum, it exhibited an excellent inhibition effect on biofilm formation for a long period of time (Figure 28b). This artificial enzymebased system was also appropriate for the destruction of preformed biofilms (Figure 28c). So far, the current studies on nanozymes with antibacterial activity are mainly focused on peroxidase mimics. However, in living systems, the antibacterial process may require the involvement of multiple enzymes. Therefore, it is of great significance to explore novel enzyme mimics with excellent antibacterial properties. Z


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peroxidase-, catalase-, as well as superoxide dismutase-like properties.97 With the multienzyme-like abilities, the N-PCNSs were able to regulate reactive oxygen species. Previous studies have demonstrated that hollow human H-ferritin (HFn) nanoparticles could specifically recognize overexpressed HFn receptor in tumor cells, delivering the complex into lysosomes.565,566 Therefore, through the conjugation of HFn on N-PCNSs, the obtained nanocomposites could efficiently reach lysosomes through receptor-mediated endocytosis (Figure 29). Under this condition, the N-PCNSs could exhibit

However, current therapy systems often need the assistance of oxygen or external stimuli to produce reactive oxygen species, and these treatments are largely limited in hypoxic tumor environment. Recently, numerous nanomaterials have been reported to serve as oxidase, peroxidase, glutathione peroxidase, catalase, as well as superoxide dismutase mimics which are able to regulate the ROS levels efficiently.26−28 On the basis of that, Qu and co-workers successfully prepared a biomimetic nanoflower through the self-assembly of different nanozymes.92 In their system, PtCo nanoparticles were synthesized first and then used to guide the growth of MnO2 nanocomponents. After adjusting the ratio of each component, MnO2@PtCo nanoflowers were fabricated (Figure 30a). PtCo nanoparticles could serve as oxidase mimics for the generation of toxic ROS under acidic tumor environment while MnO2 nanomaterials possessed excellent catalase-like property to catalyze H2O2 to O2.71,91 Therefore, under the tumor hypoxia environment, MnO2-mediated O2 generation could promote the therapy efficiency of PoCo component. Through ROSmediated cell apoptosis, the nanozyme composite could achieve excellent efficiency for cancer therapy under both normal and hypoxic conditions without any external stimuli (Figure 30b). Although nanozymes exhibit great prospects in cancer therapy, their biological safety is still a problem. There is still a long way to go for nanozymes to use for clinical treatment. 5.4. Nanozymes in Antioxidation

ROS, such as O2•−, •OH, and H2O2, are all the byproducts of cell metabolism.568,569 At low level, these ROS can serve as important second messengers and participate in many signaling processes.570 However, once the reactive oxide species are overexpressed, they may lead to many adverse reactions. For example, excessive ROS will induce some oxidative damages to lipids, proteins, DNA, and other biological molecules. In addition, they can induce caspase to activate cell apoptosis.571 What’s more, these reactive oxide species are also associated with many pathological conditions such as neurodegeneration, cancers, diabetes, atherosclerosis, arthritis, and kidney diseases.572−574 It is well-known that ROS are direct

Figure 29. Ferritin-mediated targeting delivery of N-PCNSs for cancer therapy. Reprinted with permission from ref 97. Copyright 2018 Nature Publishing Group.

excellent oxidase- and peroxidase-like abilities for the generation of toxic reactive oxygen species, suppressing the growth of tumor tissue effectively in human tumor xenograft mice models. Reactive oxygen species (ROS) induced apoptosis is a promising strategy for the treatment of malignant tumors.567

Figure 30. (a) Preparation of MnO2@PtCo nanozymes; (b) MnO2@PtCo nanozymes could serve as excellent nanomedicines for cancer therapy both under normoxia and hypoxia condition. Reprinted with permission from ref 92. Copyright 2018 Nature Publishing Group. AA


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Figure 31. Self-assembly of dual-enzyme nanocomposite for cytoprotection. (a) SP1 was used as the template for assembling GPx catalytic center to form SeSP1; (b) SOD catalytic center was modified on the surface of PD5 to form MnPD5; and (c) preparation of dual-enzyme cooperative nanowires by self-assembly of SeSP1 and MnPD5. Reprinted from ref 593. Copyright 2015 American Chemical Society.

Gao et al. found that Pd nanomaterials could serve as both catalase and superoxide dismutase mimics to efficiently eliminate harmful ROS such as O2•− and H2O2.67 The reduction of these free radicals could effectively maintain the homogeneity of mitochondrial membrane potential and reduce the damage of ROS to intracellular important biomolecules. Recently, Lin’s group found that when gold nanoclusters were modified with amine-terminated PAMAM dendrimer (AuNCs-NH2), the obtained nanomaterials could still retain their catalase-like activity while the peroxidase-like activity was lost under physiological conditions unexpectedly.582 With the unique catalase-like ability, the AuNCs-NH2 could effectively transform harmful H2O2 to a nontoxic product. Further studies demonstrated that the nanozyme could protect primary neuronal cells against ROS-induced oxidative damage. In addition, Li, Zhang, and co-workers successfully applied MoS2 nanodots with catalytic properties of catalase and superoxide dismutase for radiation protection.583 Nowadays, ionizing radiation has been widely used in industrial and medical fields.584 Despite that, ionizing radiation may be accompanied by an invasion of free radicals and DNA damage, inducing serious harm to human health.585 To this end, it is of great significance to design highly efficient and low-toxicity radiation protection agents with renal clearance property. Inspired by that, they prepared ultrasmall cysteine-protected MoS2 nanodots as radiation protection agents for removing harmful ROS during the ionizing radiation process.583 In addition, these MoS2 nanodots could efficiently repair DNA damage as well as restore important chemical and biochemical indicators. Furthermore, due to their ultrasmall size, 80% MoS2 nanodots could be excreted through the urine after 24 h of injection, and no obvious adverse reactions were found even after 30 days of injection. As mentioned above, GSH is the most important biosulfhydryl group in cells which participates in the process

participants in human diseases, aging, and death, which seriously affect human life and health. Therefore, the regulation of ROS level is of great significance to maintain intracellular redox homeostasis. In the cell system, there are several kinds of antioxidant enzymes, such as catalase, superoxide dismutase, glutathione peroxidase, peroxiredoxin, etc.575−578 These antioxidant enzymes play important roles in maintaining cellular redox balance. Though promising, under pathological conditions, overexpressed ROS will reduce the activities of enzymes, so that intracellular antioxidant mechanism is not sufficient enough to balance the excessive ROS level.579 Since many nanomaterials have the antioxidant enzyme-like catalytic activities, it may be a feasible method to use nanozymes to remove intracellular overexpressed ROS. 5.4.1. Nanozymes in Cytoprotection. Platinum (Pt), as one of the most widely used industrial catalysts, has attracted growing attention up to now. Previous studies reported that Pt NPs could serve as both CAT and SOD mimics to scavenge toxic H2O2 and O2•−.66 Traditional methods often used surfactants such as poly(acrylic acid) (PAA)580 in the preparation process to enhance their biocompatibility. Nie et al. used an apoferritin (apoFt) protein shell as the nanocarrier to in situ synthesize Pt nanostructures.66 The obtained ferritin−platinum nanoparticles were bioactive, nontoxic, and stable with excellent catalase-like activity to catalyze the decomposition of H2O2. Recently, Pompa et al. further explored their potential application in nanomedicine.581 In their work, cytocompatible Pt NPs were successfully synthesized by using citrate as the capping agents. The citrate-capped Pt nanoparticles endowed excellent SOD-, CAT-, and peroxidase-like ability that could down-regulate intracellular enhanced ROS level caused by loss-of-function mutations of ccm genes, protecting cell components against oxidative stress. Their findings showed potential applications for Pt-based nanozymes in nanomedicine and therapy. AB


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Figure 32. Multienzyme-like property of PB nanoparticles in vitro. Reprinted from ref 39. Copyright 2016 American Chemical Society.

of redox balance and sulfide formation.586,587 GSH can contribute to maintain the function of normal immune system with antioxidation and detoxification. GPx is a GSH-dependent antioxidant enzyme which is distributed in the cytoplasm and mitochondria of the cell.588,589 GPx can catalyze peroxides such as H2O2 to form nontoxic products in the presence of GSH.590 In this way, it plays an important role in maintaining intracellular redox homeostasis. Up to now, GPx mimicking is mainly focused on the design of selenium-based organic molecules.348,349,591 However, these organic molecules may have disadvantages such as complicated preparation process, high toxicity, low cycling efficiency, etc. Therefore, developing novel and biocompatibility GPx mimics is of great significance. By self-assembly the catalytic center of natural GPx on the tobacco mosaic virus (TMV) protein monomers, Liu and colleagues successfully constructed artificial nanoselenoenzymes.592 The obtained nanocomposites exhibited excellent GPx-like property that could efficiently transfer toxic hydroperoxides to harmless products with the assistance of GSH. Since the self-assembly could incorporate the active center and recognition site onto the natural protein frameworks as well as ensure the nanocomposites with high catalytic property, the catalytic ability of this nanozyme was even close to the level of natural GPx. Due to the advantages of natural protein scaffolds, this artificial nanozyme possessed remarkable biocompatibility and low immune responses in biological organisms. Cell experiments further indicated that TMV-based nanoselenoenzyme could efficiently eliminate harmful ROS and protect intracellular components such as mitochondria against oxidative damage. This work may have potential applications for antioxidative diseases such as aging and cardiovascular disease. On the basis of the above work, through the self-assembly of proteins with polymers, Liu and colleagues further constructed dual-enzyme nanocomposite for cytoprotection.593 In their system, the catalytic centers of GPx and SOD were assembled into cricoid proteins (SP1) and polymer nanoparticles (PD5), respectively (Figure 31, panels a and b). Through electrostatic interaction, the proteins and polymers could self-assemble to form cooperative nanowires with both GPx- and SOD-like

properties (Figure 31c). The generated nanocomposites could scavenge overexpressed ROS such as O2•− and H2O2, maintaining the intracellular redox balance as well as protecting the body against oxidative damage. Besides, Qu, Ren, and co-workers designed a GO-Se nanozyme with excellent GPx-like antioxidative capacity for cytoprotection.287 In their work, GO was used as the template for in situ generation of selenium nanoparticles. Because of the large area and rapid electron transfer property of GO, the asprepared GO-Se nanocomposites exhibited enhanced catalytic ability to remove toxic H2O2 effectively. In vitro studies demonstrated that GO-Se nanozyme could lower the ROS level in Rosup treated cells. In order to further explore their cytoprotection, the influence of GO-Se nanozymes on lipid peroxidation was investigated. With the assistance of GO-Se nanozyme, the ROS-induced damage on lipids was efficiently alleviated. This nanozyme presented extraordinary antioxidant ability and might have potentials in inflammatory treatments. Recently, Xu and colleagues synthesized selenium-functionalized graphene oxide (GOSe) through covalent modification of a diselenide-containing small molecule (HOEG4Se)2 onto the surface of GO nanosheets.288 Due to the property of selenium for regulating the redox balance, this GOSe could effectively catalyze the reduction of peroxides to maintain the homeostasis when intracellular ROS were overexpressed. In addition, they also successfully constructed selenium-doped carbon quantum dots (Se-CQDs) through hydrothermal method.286 The Se-CQDs exhibited a strong green fluorescence at 490 nm upon 398 nm excitation. On the basis of the significant roles in antioxidant defense and redox homeostasis regulation of selenium, the Se-CQDs showed a strong scavenging property for •OH. In vitro experiments further confirmed that Se-CQDs could efficiently remove overexpressed ROS to protect cell components from oxidative damage. In 2014, Mugesh, D’Silva, and co-workers surprisingly found that V2O5 nanowires could also serve as GPx candidates.33 With this unique property, V2O5 nanowires could scavenge intracellular overexpressed ROS and protect cellular components against oxidative damage without disturbing the cellular AC


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Figure 33. Zr4+-doped CeO2 nanoparticles with excellent antioxidant efficiency for alleviating disordered inflammation responses. Reprinted with permission from ref 605. Copyright 2017 Wiley-VCH.

antioxidant defense system. On the basis of this discovery, this biocompatible V2O5 nanowire may have potential for the treatment of aging, heart disease, and multiple neurological diseases. This work is a breakthrough for glutathione peroxidase mimics since previous work is mainly focused on selenium-based materials. All these findings open new ways for GPx mimicking, broaden the study of nanozyme as well as deepen our understanding of GPx. Nevertheless, the use of nanomaterials as GPx mimics and their use for disease treatments are still in the early stage. We still need to devote our efforts for further explorations. 5.4.2. Nanozymes in Alleviating Inflammation. Inflammation is the response to a local tissue of the damaged body which includes acute and chronic inflammation.594,595 The inflammation response is usually a precursor to some diseases. Therefore, the treatment of inflammation can effectively prevent the occurrence of related diseases such as cancers and cardiovascular diseases. An important feature of inflammatory tissue is the rise of reactive oxide species. Therefore, scavenging overexpressed ROS can relieve inflammation as well as inhibit the occurrence of related diseases. PB, with a structural formula of A[FeIIIFeII(CN)6] (A = Na+ or K+), has commonly served as a blue dye since its first preparation in 1706.596 Due to the outstanding biocompatibility and biosecurity, PB has been used as a clinical antidote for thallotoxicosis approved by Food and Drug Administration (FDA).597 In addition, the strong absorbance in the NIR and the mutual transition between Fe2+ and Fe3+ provide PB NPs additional functions for cancer diagnosis and treatment, for example, ultrasound (US) imaging, photoacoustic (PA) tomography, magnetic resonance imaging (MRI), and photothermal therapy.598−600 Recently, Gu et al. discovered that Prussian blue nanoparticles, with multienzyme-like properties, could effectively decrease intracellular ROS level and achieve excellent cytoprotection efficiency (Figure 32).39 They explained that this ROS scavenging property of PB nanoparticles was due to their affinity for hydroxyl radicals and their ability to mimic three enzymes: superoxide dismutase, catalase, and peroxidase. In vivo experiments further indicated that PB nanoparticles exhibited anti-inflammatory effects on lipopolysaccharide-induced mice hepatitis model. All these results demonstrated their unique features in ROS-induced inflammatory or injury.

Sepsis is a life-threatening organ dysfunction which results from the disordered host response to infection.601 Local infections caused by microorganisms can lead to systemic inflammation accompanied by fever and increased white blood cells as host defense mechanisms.602 If appropriate treatment is not performed within a short time, the host’s immune response can be disorganized, resulting in excessive expression of proinflammatory cytokines, multiorgan dysfunction, and even death.603 Therefore, in addition to killing bacteria, the inhibition of abnormal inflammation response is also of great significance. Since the formation of a large amount of reactive oxygen species in sepsis is the main cause of multiorgan failure, reducing the ROS level in inflammation tissue can be considered as a key goal to prevent sepsis. In the past decade, CeO2 nanoparticles have been used as potential antioxidants for treating ROS-related diseases.101,604 The unique properties of CeO2 nanoparticles are derived from their autocatalytic abilities. They can serve as enzyme mimics and maintain excellent antioxidative effects within a long period of time. Although promising, the potential toxicity limits their further applications. Since the toxicity is associated with the intrinsic properties of CeO2 nanoparticles, reducing the dose of nanoparticles is a feasible method for biomedical applications. However, when reducing the dose, it requires increasing the catalytic ability of CeO2 nanoparticles without affecting the therapeutic effect.605 The catalytic activity of ceria nanoparticles against ROS is determined by several factors: their size, the atomic ratio of surface Ce3+ to Ce4+, the conversion rate between Ce3+ and Ce4+, etc.101 Inspired by these unique features, Hyeon, Lee, and co-workers successfully prepared Zr4+-doped CeO2 nanoparticles (7CZ NP) with an average size of 2 nm.605 Zr4+ was found to effectively modulate the ratio of Ce3+ to Ce4+ and the conversion rate between them. In this way, the obtained 7CZ NP would achieve enhanced free radical scavenging capacity. To verify the potential antioxidative ability of 7CZ NP, two inflammatory-related disease models were constructed: lipopolysaccharide-induced endotoxemia rat model and the cecal ligation and puncture-induced bacteremia mouse model. Their results demonstrated that 7CZ NP could efficiently decrease the ROS level in inflammation tissues and alleviate the inflammation response in both inflammatory models (Figure 33). This novel nanomaterial could be considered as a potential ROS scavenger that would AD


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Figure 34. (a) The preparation of V2O5@pDA@MnO2 nanozymes and (b) the reactive oxygen species removal progress of SOD-CAT-GPx synergetic system and the scheme of multinanozymes system to mimic the intracellular antioxidant enzyme-based defense system. Reprinted with permission from ref 71. Copyright 2016 Wiley-VCH.

amine were used as the models to mimic intracellular antioxidant enzyme and nonenzymatic biomolecule, respectively. On the basis of the GPx-like property of nanoselenium and the reducibility of polydopamine, the obtained Se@pDA nanozyme exhibited outstanding free radical scavenging ability for cytoprotection. Then, a lipopolysaccharide-induced mouse lung inflammation model was constructed to further explore their potential applications. With the assistance of Se@pDA nanozymes, the inflammation response was efficiently alleviated, indicating the possibilities for anti-inflammation therapy. 5.4.3. Nanozymes in Treating Alzheimer’s Disease. Alzheimer’s disease (AD), one of the most common types of dementia, influences around 10% of the elderly (over 65 years old).611,612 The accumulation of amyloid protein (Aβ) plaques and neurofibrillary tangles in the brain are two main pathological indicators of AD.613 Although many researches have demonstrated that Aβ is associated with numerous molecular signaling pathways, there is no specific explanation how Aβ increases the pathogenesis of AD. In addition, the mitochondrial dysfunction induced by Aβ is also considered as a possible cause of AD through abnormal expression of ROS.614−616 Since ROS-induced mitochondrial dysfunction occurs earlier than the formation of Aβ plaque in the brain, protecting the mitochondria from oxidative damage would be useful for prevention and early treatment of AD. As discussed above, CeO2 nanoparticle with an average size of less than 5 nm, possesses outstanding SOD- and CAT-like catalytic properties.101 It can effectively eliminate O2•− and H2O2 and protect cells from oxidative stress. This is mainly because CeO2 can bind oxygen atoms in a recyclable way as well as the rapid conversion between Ce4+ and Ce3+ on the surface of nanoparticles. Recently, Hyeon et al. designed triphenylphosphonium (TPP)-modified CeO2 nanoparticle as a new platform for AD treatment.617 The obtained nanocomposite could localize to mitochondria and then eliminate harmful ROS, inhibiting the neuronal death in a 5XFAD

confront the infection directly and alleviate disordered inflammation responses. In living systems, enzymes are not always working alone, and many enzymes may participate in the same life process.78 For example, the intracellular antioxidant defense system requires the cooperation of antioxidases such as SOD, CAT, and GPx to maintain intracellular redox balance.606,607 To mimic this enzyme-based antioxidant defense system, Qu and Ren’s groups constructed a powerful multinanozyme-based composite which could remove overexpressed ROS effectively and protect the body against oxidative damage.71 In their work, V2O5 nanowires and MnO2 nanoparticles were used as nanozyme models (Figure 34a). V2O5 nanowires possess excellent GPx-like property that can catalyze H2O2 to H2O with the assistance of GSH. Meanwhile, MnO2 nanoparticles can serve as SOD and CAT mimics to eliminate harmful reactive oxide species. Through the linking of polydopamine (pDA), the obtained V2O5@pDA@MnO2 exhibited multiantioxidase-like abilities that could mimic an intracellular SOD, CAT, GPx, etc. coconstructed antioxidant defense system (Figure 34b). Besides, pDA could also serve as an antioxidant for ROS removing.608,609 Thus, by combining the antioxidative abilities of nanozymes and pDA, the V2O5@pDA@MnO2 nanocomposites exhibited a synergistic ROS scavenging effect that would protect cell components against oxidative damage. To further explore the potential of the nanocomposites, phorbol 12-myristate 13-acetate (PMA)-induced mouse ear inflammation model was designed. The results demonstrated that the V2O5@pDA@MnO2 nanocomposites could efficiently decrease the ROS level as well as alleviate inflammationinduced adverse effects on mouse. Subsequently, they constructed a self-assembly nanocomposite to mimic intracellular antioxidant defense machinery.289 In living systems, antioxidant enzymes as well as nonenzymatic antioxidant biomolecules coparticipate in the balance of fantastic intracellular redox.71,610 To mimic this antioxidant defense machinery, nanoselenium and polydopAE


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transgenic AD mouse model. In addition, the TPP-modified CeO2 nanoparticles could also alleviate reactive neuroglia and mitochondrial damage. Further exploration demonstrated that their system could be used as a new method of mitochondrial therapy for neuroinflammation, which was of great significance for the treatments of Alzheimer’s disease and other neurodegenerative diseases. The accumulation of Aβ induced by protein misfolding has been considered the hallmark for neurodegenerative disease.618,619 Although much effort has been devoted to screening natural proteases to degrade Aβ, it is still difficult to apply them to actual clinical applications due to the existence of intractable biological immunogenicity problems. Inspired by the unique features of nanozymes, by selfassembling CeO 2 nanoparticles and polyoxometalates (POM), Qu and co-workers successfully designed CeONP@ POMs hybrid nanomaterials recently.319 The nanocomposites exhibited a SOD-like antioxidant property and could also serve as proteolytic enzyme mimics. In this way, CeONP@POMs could efficiently inhibit the aggregation of Aβ as well as decrease the intracellular ROS level. Furthermore, through immunoassay and flow cytometry, the CeONP@POMs were found to promote the proliferation of PC12 cells, and at the same time, effectively inhibit the activation of BV2 microglial cells caused by Aβ. A large number of studies have indicated that high concentrations of metal ions (such as Cu2+ and Zn2+) play a significant role in the accumulation of Aβ deposition and its neurotoxicity.620,621 Studies have also confirmed that ROS can mediate the apoptosis of neurons, leading to the formation of senile plaques gradually.622 In addition, the formation of oxidant-induced Aβ oligomers is considered to be another important factor in neuronal dysfunction and apoptosis. Therefore, oxidative damage and metal ion disorders can be used as targets for AD therapy. Inspired by this, Qu and coworkers constructed a bifunction delivery system for the treatment of AD by combining Cu2+ chelator and CeO2 NPs.298 In their system, mesoporous silica was used as the carrier to load Cu2+ chelator clioquinol (CQ). Glucose-coated CeO2 NPs (G-CeO2NPs) could bind to boronic acidfunctionalized mesoporous silica through boron ester bond.623,624 In this way, G-CeO2 NPs could serve as gatekeepers which efficiently inhibit the leakage of chelators. In the presence of H2O2, it could break the boron ester bond, inducing the release of Cu2+ chelator. Therefore, it could efficiently prohibit the aggregation of Aβ. Furthermore, with the antioxidant enzyme-like catalytic capacity of CeO2 NPs, this nanocomposite could achieve a synergistic AD therapy effect to scavenge overexpressed ROS. Besides, ferromagnetic nanoparticle can also be used as a free radical scavenger to relieve ROS-associated neurodegenerative diseases. Recently, Fan et al. further studied the in vitro and in vivo antioxidant influences of Fe3O4 NPs (Figure 35).625 For in vitro tests, two cell lines (L929 cells and PC12 cells) were used in their work and L929 cells were first investigated. After 12 h incubation for L929 cells with Fe3O4 NPs, the NPs were internalized and finally located at cytosol. In this neutral environment, Fe3O4 NPs with catalase-like property could efficiently scavenge intracellular excessive ROS and protect L929 cells against H2O2-induced oxidative damage and apoptosis. They also discussed the neuroprotection effects of Fe3O4 NPs on PC12 cells. Cell studies demonstrated that Fe3O4 NPs could efficiently alleviate 1-methyl-4-phenyl-

Figure 35. Antioxidant property of Fe3O4 NPs to delay animal aging and ameliorate ROS induced neurodegeneration. Reprinted with permission from ref 625. Copyright 2016 Wiley-VCH.

pyridinium (MPP+)-induced cell death as well as diminish the protein levels of α-Synuclein and Caspase-3 activation. For in vivo studies, they designed the drosophila model to investigate the influence of Fe3O4 NPs. After feeding drosophila with food containing Fe3O4 NPs, the drosophila showed enhanced climbing ability and extended life span. The drosophila AD model further verified the excellent antioxidant property of Fe3O4 NPs to delay animal aging and ameliorate ROS-induced neurodegeneration (Figure 33). 5.4.4. Nanozymes in Treating Parkinson’s Disease. Similar to Alzheimer’s disease, Parkinson’s disease (PD) is also a common neurodegenerative disease which often occurs in the elderly.626 The most important pathological changes of PD is the massive cell death of the neuromelanin-containing dopaminergic neurons of the substantia nigra, resulting in significant reduction in the content of the striatum DA.627 Nowadays, the exact cause of this pathological change remains unclear; genetic factors, environmental factors, aging, and oxidative stress may participate in the degeneration death process of the PD dopaminergic neuron. Recently, Mugesh, D’Silva, and co-workers demonstrated that Mn3O4 nanoparticles with flower-like morphology possessed multiantioxidant-enzyme-like catalytic activities which could play a crucial role in protecting human cells from MPP+ induced cytotoxicity in a PD-like cellular model.108 Inspired by this work, Kuang and colleagues further designed phenylalanine-modified CuxO nanoclusters for PD treatment.628 Since copper serves as a vital component of many important enzymes in living systems, the formed CuxO nanoclusters exhibited multienzyme-like properties (SOD, CAT, and GPx) which could efficiently remove harmful ROS and protect nerve cells against oxidative stress induced by MPP +. To further explore the potential therapeutic efficiency for PD, a mouse model of Parkinson’s disease was constructed. After the injection of CuxO nanoclusters, the levels of ionized calcium-binding adapter molecule 1 and tyrosine hydroxylase were both obviously decreased compared with the untreated PD mouse. In addition, the spatial learning as well as memory AF


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Figure 36. Using M-HFn nanozymes for staining tumor tissues. Reprinted with permission from ref 565. Copyright 2012 Nature Publishing Group.

efficiently distinguish cancer cells and normal cells with ultrahigh sensitivity and specificity when examining practical clinical specimens. This work suggests that nanozymes may have great potential for disease diagnosis. On the basis of Yan and Liang’s work, Pan and co-workers doped cobalt into the M-HFn nanoparticles.630 By controlling the amount of cobalt component, the obtained nanocomposites could exhibit enhanced peroxidase-like ability to visualize tumor tissues with higher efficiency. In addition to the colorimetric method, Zhao and colleagues used nanomaterial/DNA integrated systems to achieve the fluorescence imaging of intracellular base-excision repair (BER).631 They chose MnO2 nanosheet/DNAzyme for their research work. MnO2 nanosheet could serve as both nanocarriers for DNA delivery and the cofactor of DNAzyme. DNAzyme and damaged bases containing excision probes were first hybridized. The formed duplexes and substrate probes (containing with fluorescent groups and corresponding quenchers) were then coadsorbed on the surface of MnO2 nanosheets. When the nanocomposites were uptaken by cells, the MnO2 nanosheets could be reduced into Mn2+ in the presence of GSH, and both the excision/DNAzyme duplexes and substrate strands were released from the nanosheets. The specific BER enzymes in different pathways could identify and excise the damaged base components, leading to the release of DNAzyme strands. In the presence of a Mn2+ cofactor, the catalytic activity of DNAzymes was activated. Therefore, the DNAzymes could efficiently excise corresponding substrate and the fluorescence signal was recovered finally. In this way, the BER pathways could be monitored through the changes of fluorescence signals. Besides, Cai et al. successfully designed FA-functioned AuNCs for tumor molecular colocalization diagnosis.632 Since AuNCs possessed excellent fluorescence

ability of the PD mice model were also studied. Compared with the PD mice, the CuxO nanoclusters treated mice displayed strongly enhanced spatial learning, memory, escape latency, and swimming speeds during the training process, indicating that CuxO induced cognitive recovery in these mice. Taken together, this powerful CuxO antioxidant nanozyme might have great potential for ameliorating neurodegeneration diseases. Briefly speaking, numerous nanozymes have been found to possess inherent antioxidant enzyme-like activities. On the basis of that, they can be used for cytoprotection, alleviating inflammation as well as treating neurodegeneration diseases. All these studies have made great contributions to the development of nanozymes in future clinical applications. 5.5. Other Applications

Nanozymes can also be used for other novel applications such as imaging, antithrombosis, individual living cell encapsulation, etc.60,128,565 With the deep understanding of nanozymes, these novel artificial enzymes will be applied to more new fields. 5.5.1. Nanozymes in Imaging. Nanozymes can be used for targeting and visualizing tumor tissues.565 To achieve this goal, Yan, Liang, and co-workers designed magnetoferritin nanoparticles (M-HFn) by encapsulating iron oxide nanoparticles into a recombinant human heavy-chain ferritin protein shell (Figure 36). Because of the unique properties of the HFn component as well as iron oxide nanoparticles, the formed M-HFn could be used for targeting and visualizing tumor tissues629 without the addition of contrast agents or targeting ligands. HFn could specifically identify overexpressed transferring receptor 1 in tumor tissues while the iron oxide nanocomponents could catalyze the oxidation of TMB with the assistance of H2O2 to generate blue products for visualizing tumor tissues. The magnetoferritin nanoparticles could AG


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(HNO).128 When NADPH and O2 are replaced by H2O2, the biocatalytic reaction can still be carried out successfully. Similar to NO, HNO also has an antithrombotic property. Therefore, biomimetic generation of HNO from endogenous substances may be one possible way for antithrombosis. Inspired by these unique properties, Duan et al. designed grapheme-hemeinglucose oxidase nanocomposites for antithrombosis (Figure 37).128 In their work, grapheme nanosheets were used as the

imaging and peroxidase-like activities, this system could achieve tumor tissues fluorescence/visualizing detection by combining with the cancer cells targeting ability of FA. This powerful nanoprobe could effectively improve the accuracy of cancer diagnosis which might contribute to the further cancer therapy. Furthermore, Tremel, Tahir, and co-workers found that MnO nanoparticles with SOD-like property could serve as potential MRI agents with improved contrast.633,634 Their results demonstrated that when the concentration of Mn element was 5 mM, the T1 and T2 of the MnO contrast agent were 501 and 39 ms, respectively. The corresponding specific relaxivities were r1 of 0.35 ± 0.01 and r2 of 4.94 ± 0.11 mM−1 s−1. In the presence of O2•−, obviously increased T1 and T2 relaxation times were measured, and their corresponding r1 and r2 values were 0.06 ± 0.01 and 1.90 ± 0.14 mM−1 s−1, respectively. This change of paramagnetic field might be due to the temporary change of the oxidation states of manganese ion component when catalyzing the disproportionation of O2•−. With the unique SOD-like property as well as enhanced MRI contrast, this MnO nanoparticle shows potential for disease diagnosis and treatment. Gu and co-workers also used PB nanozymes for US and magnetic-resonance (MR) dual modality imaging of H2O2 in living system.635 Since PB nanoparticles could efficiently catalyze the decomposition of overexpressed H2O2 to O2 in tumor tissues, the formed gas molecules could be used as ultrasound contrast agents (UCA) to improve the performance of US imaging. In this way, the nanozyme-based system was able to change oxidative stress-induced acoustic impedance and enhance the signal of US imaging. In addition, PB nanoparticles could also serve as T1 MRI contrast agents owning to their unique properties and structures. This dualmode imaging system might provide a universal nanoplatform for investigation of H2O2 generation both in vitro and in vivo. In addition, Choi et al. constructed porous platinum nanozymes with a high atomic number and excellent catalytic ability for oxygen generation to achieve enhanced radiotherapy performance in vivo.636 This nanozyme-based system could efficiently deposit the X-ray radiation energy in tumor tissues, leading to the increased DNA damage, oxidative stress, as well as cell cycle arrest. Besides, the generation of O2 molecules could further improve the radiotherapy efficiency since oxygen was needed during the process. This platinum-based nanozymes could serve as a potential nanomedicine with enhanced radiotherapy efficiency for cancer therapy. 5.5.2. Antithrombosis. Thrombosis is one of the most common and serious problems that cause complications of blood upon contacting with biomedical devices. One potential solution is designing antithrombotic coatings on these devices to efficiently inhibit the formation of thrombosis.637 Since nitric oxide (NO) is an effective antiplatelet agent to prevent thrombosis, numerous efforts have been dedicated to the fabrication of polymeric coatings that can release or generate NO.638 Although promising, these methods are not suitable for long-term implants because of the limited exogenous NO donor source. Besides, these NO donors often need external stimulation to release NO.639 The toxicity of some precursors as well as their byproducts is also a problem worth considering. It is well-known that in life systems, nitric oxide synthase enzymes can catalyze L-arginine and O2 to produce NO with the assistance of the cofactor NADPH.640 In some cases, the reaction is also accompanied by the formation of nitroxyl

Figure 37. Grapheme-hemein-glucose oxidase nanocomposites for biomimetic generation of HNO. Reprinted with permission from ref 128. Copyright 2014 Nature Publishing Group.

template to assemble glucose oxidase as well as hemein. Glucose oxidase could catalyze endogenous glucose to produce H2O2167 while the hemein component could serve as the nitric oxide synthase enzyme mimic641 to further catalyze the oxidation of L-arginine with the assistance of H2O2 to generate antithrombotic HNO under physiological environments. When integrating grapheme-hemein-glucose oxidase nanocomposites into polyurethane, the obtained polymeric coatings could achieve a long-lasting antithrombotic efficiency. 5.5.3. Individual Living Cell Encapsulation. Recently, the single cell encapsulation technique has attracted much attention for biosensing, biocatalysis, as well as cancer therapy.642,643 In order to preserve the viabilities and functions of cells in harsh environments, a growing effort has been devoted to developing powerful coating shells, for example, silica, calcium phosphates, polymers, etc.60 Though promising, there still remains some problems when apply those coating shells into practical systems. Due to their inherent inertness and permeability, those coatings shells may have limited protecting abilities against toxic chemicals, such as ROS, which may induce oxidative stress to intracellular components and can even lead to cell death. In addition, the outer shells often need strong stimulation to decompose, which may cause serious damage to the cells. Therefore, developing biodegradable coating shells with cytoprotection function against harsh environments is highly desired. Considering the unique properties of nanozymes, Qu and Ren’s groups successfully constructed a novel individual living cell encapsulation system.60 In their work, MnO2 nanozymes served as the intelligent nanoshells for cytoprotection. Through biomineralization,644,645 MnO2 nanomaterials were coated around individual yeast cell without obvious damage. With the unique antioxidant enzyme-like properties of MnO2, the nanozymeAH


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method for hyperuricemia is enzyme replacement therapy.650,651 Since uricase can catalyze the decomposition of uric acid, uricase-based therapy will efficiently decrease the level of uric acid in plasma.652 Though promising, the poor stability of enzymes as well as the toxic byproduct H2O2 may strongly limit its practical applications. To solve this problem, Qu and co-workers designed a novel metalloenzyme based on uricase and antioxidant nanozyme.653 In their system, mesoporous silica was used as the nanocarrier for assembling uricase and Pt nanoparticles. Mesoporous silica could protect uricase against the interference of the surrounding environment.654 Uricase component could efficiently catalyze the decomposition of uric acid while Pt nanoparticles would transform toxic H2O2 to harmless product. This obtained artificial metalloenzyme could achieve excellent treatment efficiency for hyperuricemia with no obvious side effects. This work may promote the development of nanozymes for disease treatment. 5.5.6. UV-Protective Sunscreens. Nanozymes can also be used for sunscreens against UV damage.655 It is well-known that long-term ultraviolet radiation can cause oxidative damage or even induce skin cancers in some cases.656 For this reason, sunscreen is very important. The use of sunscreen can effectively alleviate the skin damage caused by ultraviolet radiation. Traditional sunscreens mainly contain ZnO or TiO2.657,658 These metal oxides can reflect or scatter harmful ultraviolet light and protect the skin against oxidative damage. However, both zinc oxide and titanium dioxide are semiconductors which exhibit excellent photocatalytic activity.659 Under the ultraviolet radiation, toxic reactive oxygen species are generated, leading to oxidative damage to the skin. To alleviate this problem, Qu and Ren’s groups introduced antioxidant nanozyme into the ZnO sunscreen agent.655 In their work, CeOx nanoparticles were chosen as the antioxidant enzyme models because of their excellent antioxidant activities. After assembling ZnO and CeOx nanoparticles, ZnO/CeOx hollow microspheres (ZnO/CeOx HMS) were formed. Combined with the broad-spectrum UV protection and excellent ROS scavenging ability, the obtained ZnO/CeOx HMS could efficiently protect cells against UV irradiation. Furthermore, when adding ZnO/CeOx HMS into sunscreen, it could ameliorate UV-induced damage in mouse skin more efficiently compared with sunscreen alone, sunscreen-containing ZnO nanoparticles, or sunscreen with CeOx nanoparticles. This work demonstrated that ZnO/CeOx HMS could be a potential UV-protective sunscreen candidate for skin protection. Taken together, nanozymes, as potential candidates for natural enzymes, have been well-acknowledged, and their application fields are gradually expanded.660−703

based shells could efficiently eliminate harmful ROS and protect intracellular components against oxidative stress. In addition, the coated yeast cells could also achieve enhanced cellular tolerance from numerous physical pressures. Different from other encapsulation strategies, the nanozyme-based shells could be efficiently removed under biomolecule stimuli, for example, the presence of GSH. After the removal of nanozyme shells, the yeast cell could fully restore the growth, and the functions were not affected. This could be a general strategy for cytoprotection of a broad range of living cells. 5.5.4. Bioorthogonal Catalysis. Bioorthogonal chemistry is a promising method which can produce molecules in the cells for imaging and cancer therapy.44 However, this is unattainable through natural biological processes. It is wellknown that transition metal catalysts can be used for bioorthogonal catalysis.409 However, these materials often suffer from shortcomings such as poor biocompatibility, water solubility, and stability. They may also be effluxed from living cells rapidly. These problems can be effectively avoided after assembling these transition metal catalysts into nanomaterial skeletons. Recently, by intercalating hydrophobic transition metal catalysts into hydrosoluble AuNPs, Rotello’s group successfully designed a protein-sized bioorthogonal nanozyme for imaging and killing cancer cells.43 In their work, AuNPs were modified with three functional groups: (1) a hydrophobic alkane chain for inserting hydrophobic transition metal catalyst, (2) a hydrophilic tetra(ethylene glycol) unit to enhance the biocompatibility and biosecurity of nanomaterial, and (3) a dimethylbenzylammonium group to combine the cucurbituril (CB[7]) via host−guest interaction. Owning to the steric hindrance effect, CB[7] could serve as a gatekeeper that could efficiently block the catalytic property of the transition metal catalyst. With the addition of competitive guest molecules, CB[7] could release from nanoparticles, therefore, the catalytic activity of nanozyme was completely restored. In order to verify the feasibility of the design, a ruthenium complex (Ru) was selected as the transition metal model. After assembling, the obtained NP_Ru_CB[7] exhibited excellent biocompatibility which could be internalized by HeLa cells. Since Ru could catalyze nonfluorescent precursor rhodamine 110 derivative to fluorescent product rhodamine 110, no significant change in fluorescence was monitored when incubating rhodamine 110 derivative with nanozyme pretreated cells. With the addition of competitive guest molecule, 1-adamantylamine (ADA), owning to the high binding ability between ADA and CB[7], NP_Ru_CB[7] nanozyme would restore its catalytic capacity to transform rhodamine 110 derivative to fluorescence product. Under this condition, a strong fluorescent signal could be monitored in HeLa cells. This regulation of enzymatic property was then used for imaging cancer cells. After that, a palladium complex (Pd) was chosen to design NP_Pd_CB[7] nanozyme for cancer therapy. In their work, Pd could catalyze nontoxic prodrug 5-fluorouracil (5-FU) to form highly toxic 5-FU. With the assistance of ADA, the NP_Pd_CB[7] nanozyme could transform the generation of 5-FU, killing the cancer cells efficiently. This bioorthogonal catalysis can be used for therapy applications such as activating precursor drugs at the site of action as well as treating noncancerous chronic diseases. 5.5.5. Treating Hyperuricemia. It is well-known that hyperuricemia,646 caused by the overexpressed uric acid in plasma, may induce many related diseases such as arthritis, cardiovascular diseases, diabetes, etc.647−649 A promising

6. CONCLUSIONS AND PROSPECTS Since the discovery of Fe3O4 nanoparticles as peroxidase mimics in 2007, nanozymes have attracted much attention. As natural enzyme mimics, nanozymes possess many advantages such as low cost, easy preparation, excellent stability, and good durability. Up to now, they have been widely applied in sensing, environmental treatment, antibacteria, cancer therapy, antioxidation, etc. In this review, we summarized the classification, catalytic mechanism, activity regulation, as well as recent research progress of nanozymes in these fields in detail. Although nanozymes overcome many disadvantages of natural enzymes, there are several exciting challenges that still remain. (1) The high catalytic activity and excellent substrate AI


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to clinical use. (7) Natural enzymes are widely used in fields including medicine, food, industry, agriculture, environment, biotechnology, etc. Compared with natural enzymes, current research on applications of nanozymes are still rather limited. These unsolved issues will be the next frontier for further applications.

selectivity are the unique properties of natural enzymes. Although numerous nanomaterials have been proved as enzyme mimics and the catalytic activities of some designed nanozymes are comparable or even higher than those of natural enzymes, the catalytic activities of most nanozymes are still much lower than those of corresponding natural enzymes. In addition, nanozymes also have the problem of poor substrate selectivity. Researchers have realized these problems currently and relevant work has also been carried out. However, these studies are still far from enough. To this end, much effort and attention need to be paid to rationally construct novel nanozymes with high substrate selectivity as well as catalytic efficiency. (2) Up to now, the research focus on nanozymes is mainly concentrated on the mimicking of oxidoreductases, such as oxidase, peroxidase, catalase, and superoxide dismutase, while other enzymes are less studied, especially for isonanozymes and stereoselective nanozymes. In the natural environment, enzymes are mainly divided into six categories according to the types of catalytic reactions, including oxidoreductases, hydrolases, transferases, lyases, isomerases, and ligases. And in living organisms, there are numerous enzymes that collaborate and participate in many important living processes. To this end, developing more types of nanozymes and exploring their cascade reactons will deepen our understanding of natural enzymes and complex life processes. (3) Although researchers have made a lot of effort to study the catalytic mechanisms of nanozymes, just a few mechanisms have been reported so far, and many catalytic mechanisms are still unclear. Understanding the catalytic kinetics and mechanisms may benefit the regulation of catalytic activities of nanozymes. Therefore, we still need to devote more energy to exploring their catalytic kinetics and mechanisms. (4) Natural enzymes often have uniform morphologies and sizes, but the morphologies and sizes of nanozymes are often different from each other. In addition, natural enzymes usually just have one enzymatic activity, catalyzing the specific substrate or a class of analogues. However, some nanomaterials may possess multienzyme-like activities, and these activities sometimes can even interfere with each other. Moreover, unlike natural enzymes which are just used to catalyze biochemical reactions, some nanozymes may have additional properties for imaging, photothermal therapy, etc. It is still unknown whether these properties will influence the catalytic ability of nanozymes. We need to pay more attention to these issues, such as how to balance and take advange of these unique properties of nanozymes. (5) Recent studies on nanozymes are still mainly focused on sensing, and practical applications in the detection field have been just realized. Applications in other fields such as environmental protection are still in the experimental stage. Compared with natural enzymes, nanozymes with potential toxicities and relatively lower catalytic activities can still not meet the requirements of practical applications. In the environmental protection and antibacterial application, most studies are focused on the peroxidase mimics, while other types of nanozyme with catalytic degradability of organic pollutants or antibacterial activities are less reported. (6) Though nanozymes have shown potential in cancer therapy, their own biological safety is still a great concern. Similarly, the biosafety and potential toxicity remain challenging for nanozymes used for cytoprotection. Therefore, researchers need to focus on the development of low toxicity and high efficiency nanozymes for disease treatment, which is a long way for nanozymes applying

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Fax: 0431-85262656. ORCID

Jinsong Ren: 0000-0002-7506-627X Xiaogang Qu: 0000-0003-2868-3205 Notes

The authors declare no competing financial interest. Biographies Yanyan Huang received her B.S. degree in Applied Chemistry from Nanjing Normal University, China, in 2012. In the same year, she joined Professor Jinsong Ren’s group at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, and received her Ph.D. in 2018. Her work is mainly focused on the self-assembly of nanozymes and their potential biological applications. Jinsong Ren received her B.S. degree at Nanjing University in 1990 and Ph.D. from Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, in 1995. From 1996 to 2002, she worked in School of Medicine, University of Mississippi Medical Center, and Department of Chemistry and Chemical Engineering, California Institute of Technology. In 2002, she took a position as a principal investigator at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. Her current research interest is mainly focused on the design of novel nanozymes and the construction of nanomaterial-based multifunctional systems for cancer therapy. Xiaogang Qu received his Ph.D. from the Chinese Academy of Sciences in 1995 with CAS President’s Award. He moved to the United States afterward and worked with Professor J. B. Chaires at the Mississippi Medical Center and Nobel Laureate Professor Ahmed. H. Zewail at the California Institute of Technology. Since late 2002, he has been a professor at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. In 2007, he visited the group of Nobel Laureate Professor Alan J. Heeger at University of California, Santa Barbara. His current research interest is focused on ligand-nucleic acids or related protein interactions, design of novel nanomedicines for Alzheimer’s disease, and regulation of catalytic activity of nanozymes.

ACKNOWLEDGMENTS Financial support was provided by the National Natural Science Foundation of China (21431007, 21533008, 21871249, 91856205, and 21820102009) and the Key Program of Frontier of Sciences, CAS QYZDJ-SSW-SLH052. ABBREVIATIONS Aβ AA ABTS AChE AD ADA AJ

amyloid protein ascorbic acid 2,2′-azino-bis(3-ethylbenzothiazoline6-sulfonic acid) acetylcholinesterase Alzheimer’s disease 1-adamantylamine DOI: 10.1021/acs.chemrev.8b00672 Chem. Rev. XXXX, XXX, XXX−XXX

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FF@PW12@GO

AFM apoFt AR ATP ATP-Ce-Tris CPNs

atomic force microscopy apoferritin Amplex Red adenosine triphosphate ATP-Ce-Tris coordination polymer nanoparticles AuNCs Au nanoclusters AuNPs@POMD-8pep gold nanoparticles, polyoxometalate with Wells-Dawson structure and NAc-Cys-hepta-peptide complex Azo azobenzene BER base-excision repair BG Berlin green CAT catalase CAT-NP Fe3O4 nanoparticles CB[7] cucurbituril CD cyclodextrin β-CD β-cyclodextrin CdTe QDs CdTe quantum dots CeONP/POMs ceria/polyoxometalates CFMP carboxyl-functionalized mesoporous polymer CM-PtNP β-casein-stabilized Pt nanoparticle CN− cyanide ion CNA g-C3N4@AuNPs CNDs carbon nitride dots CNTs carbon nanotubes CoFe-LDHs CoFe layered double hydroxide nanoplates Co-g-C3N4 cobalt-doped graphitic carbon nitride nanomaterials CoOxH-GO cobalt hydroxide/oxide-modified graphene oxide CQ chelator clioquinol CQDs carbon quantum dots CWA chemical warfare agents Cys cysteine 7CZ NP Zr4+-doped CeO2 nanoparticles DA dopamine DFT density functional theory DMAE DNase-mimetic artificial enzyme DMNP dimethyl 4-nitrophenyl phosphate DNase desoxyribonuclease DOPA 3,4-dihydroxy-phenylalanine ds-DNA double-stranded DNA eDNA extracellular DNA ELISA enzyme-linked immunosorbent assay EMSN expanded mesoporous silica ESR electron spin resonance FA-GO-AuNCs folic acid conjugated graphene oxidegold nanoclusters FDA Food and Drug Administration FDTD finite-difference time-domain Fe3+-MCNs Fe3+-doped mesoporous carbon nanospheres FeMnO3@PPy FeMnO3 nanoparticle-filled polypyrrole Fe3O4 ferromagnetic nanoparticles Fe3O4@3DGN Fe3O4 nanoparticle loaded 3D porous grapheme nanocomposite Fe3O4-MMT Fe3O4-montmorillonite Fe3O4-MWCNT Fe3O4-multiwalled carbon nanotube

5-FU G-CeO2NPs g-C3N4 GCNT-Fe3O4 Gly-Cu(OH)2 GO GO-AuNC GO-COOH GOQDs GOSe GOx GPx GQDs GQDs/CuO GR GS GSH HCV HEL Hemin-SWCNT HFn His-AuNCs HNO HOX HPNPP HRP IMO INAzymes K3[Fe(CN)6] MC MG MGCB M-HFn Mn-NPs MNPs MOF MoO3 MoS2 MoS2-ppy-Pd MPP+ MR MRI MSN MWCNT@rGONR MWCNTs NADPH Nanozymes N-CNMs NIR NO N-PCNSs NTPs AK

diphenylalanine-H3PW12O40-graphene oxide 5-fluorouracil glucose-coated CeO2 NPs graphitic carbon nitride graphene oxide dispersed carbon nanotubes-Fe3O4 glycine-functionalized copper(II) hydroxide nanoparticles graphene oxide graphene oxide-gold nanocluster carboxyl-functioned graphene oxide nanosheets graphene oxide quantum dots selenium-functionalized graphene oxide glucose oxidase glutathione peroxidise graphene quantum dots graphene quantum dots/CuO glutathione reductase graphene-mesoporous silica glutathione Hepatitis C virus humanerythroleukemia cell line Hemin-single-walled carbon nanotubes H-ferritin histidine-modified gold nanoclusters nitroxyl hypohalous acids 2-hydroxypropyl-4-nitrophenylphosphate horseradish peroxidase International Maritime Organization integrated nanozymes potassium hexacyanoferrate (III) mesoporous carbon Malachite green Malachite green carbinol base magnetoferritin nanoparticles Mn(II)-containing silica nanoparticles ferromagnetic nanoparticles metal−organic framework molybdenum trioxide molybdenum disulfide MoS2-polypyrrole-Pd 1-methyl-4-phenylpyridinium magnetic-resonance magnetic resonance imaging mesoporous silica multiwalled carbon nanotube@reduced graphene oxide nanoribbon multiwalled carbon nanotubes nicotinamide adenine dinucleotide phosphate nanomaterial-based artificial enzymes nitrogen-doped carbon nanomaterials near infrared nitric oxide nitrogen-doped porous carbon nanospheres nucleoside triphosphates DOI: 10.1021/acs.chemrev.8b00672 Chem. Rev. XXXX, XXX, XXX−XXX

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O2

o-CNTs o-GQDs OPH PA PAA PB PB/MWCNT PB-NGS PB/PPy PD pDA PDT PEG-HCCs PEG-MoS2 PMA POM POM-MOFs Pt PTE Pt@mSiO2 PtPdNDs/GNs PTT PY rGO RGO-PMS-AuNPs RISC ROS Se-CQDs SNPs SOD Soman ss-DNA SuOx SWCNHs-COOH SWNTs TEM TMB TMV TPP UCA US VE CeO2 NPs V-HPOs V2O3-OMC VX ZnO-CNTs

Review

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singlet oxygen oxygenated-group-enriched carbon nanotubes oxygenated groups enriched graphene quantum dots organphosphorus hydrolase photoacoustic polyacrylic acid Prussian blue carbon nanotube supported prussian blue Prussian blue supported on nitrogendoped graphene Prussian blue/polypyrrole Parkinson’s disease polydopamine photodynamic therapy poly(ethylene glycolated) hydrophilic carbon clusters NFs PEG-modified MoS2 nanoflowers phorbol 12-myristate 13-acetate polyoxometalates polyoxometalate-pillared metal−organic framework platinum phosphotriesterase Pt nanoparticles in mesoporous silica PtPd nanodendrites on grapheme nanosheets Photothermal therapy Prussian yellow reduced graphene oxide AuNPs on the surface of periodic mesoporous silica-modified reduced graphene oxide RNA-induced silencing complex reactive oxygen species selenium-doped carbon quantum dots single-nucleotide polymorphisms superoxide dismutase O-pinacolyl methylphosphonofluoridate single-stranded DNA sulfite oxidase carboxylic-group-functionalized singlewalled carbon nanohorns single-walled carbon nanotubes transmission electron microscopy 3,3′,5,5′-tetramethylbenzidine tobacco mosaic virus triphenylphosphonium ultrasound contrast agents ultrasound vacancy-engineered nanoceria vanadium haloperoxidase V2O3-ordered mesoporous carbon O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate ZnO-carbon nanotubes

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Nanozymes: Classification, Catalytic Mechanisms, Activity Regulation

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