Coordination Chemistry Reviews 448 (2021) 214170

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Review

Nanozymes: Activity origin, catalytic mechanism, and biological

application
Wenping Yang a, Xin Yang b, Longjiao Zhu a, Huashuo Chu a, Xiangyang Li b, Wentao Xu a,⇑
a
Department of Nutrition and Health, and College of Food Science and Nutrition Engineering, China Agricultural University, Beijing 100191, China
b
Beijing Laboratory of Food Quality and Safety, Faculty of Food Science and Engineering, Beijing University of Agriculture, Beijing 102206, China

a r t i c l e i n f o a b s t r a c t

Article history: Nanozymes are nanomaterials with excellent enzyme-like characteristics. Compared with natural
Received 16 April 2021 enzymes, nanozymes possess significant advantages, such as low cost, high stability, good durability, con-
Accepted 15 August 2021 trollable activity, easy storage, and excellent reusability, thus they have been widely applied in industrial,
medical, and biological fields. In the past decade, nanozymes have made impressive progress in their
activity exploration, mechanism study, and advanced applications. In this review, we analyze the source
Keywords: of nanozyme catalytic activities from two aspects, including the structure comparison of natural enzymes
Nanozyme
and nanozymes and the nano effects of nanomaterials. We also systematically summarize the catalytic
Activity origin
Catalytic mechanism
mechanism of nanozymes, and discuss the reason for their multiple enzyme-like activities. In addition,
RONS regulation RONS regulation-based biological applications are comprehensively reviewed. Finally, we present the
Biological application current challenges of nanozymes and their future research directions.
Ó 2021 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Activity origin of nanozymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Enzyme-like properties of nanozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Peroxidase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2. Oxidative activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.3. Catalase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.4. Superoxide dismutase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.5. Hydrolase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.6. Diversity of nanozyme activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4. Biological applications of nanozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.1. Anti-inflammatory and cytoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.2. Neurological disease therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.3. Cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.4. Sterilization and disinfection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5. Conclusions and prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

⇑ Corresponding author at: China Agricultural University, Tianxiu Road 10, HaiDianDistrict, Beijing China.
E-mail address: xuwentao@cau.edu.cn (W. Xu).

https://doi.org/10.1016/j.ccr.2021.214170
0010-8545/Ó 2021 Elsevier B.V. All rights reserved.
W. Yang, X. Yang, L. Zhu et al.
1. Introduction
Nanomaterials typically refer to materials with size (at least in
one dimension) of 1–100 nm. At this scale, materials may exhibit
unique chemical, physical, biological, and mechanical properties
that are distinct from bulk ones.[1] The morphology of nanomate-
rials includes solid, hollow, or porous nanospheres, nanorods,
nanosheets, nanofibers, nano-polyhedrons, nanoflowers and so
on. In 1990 s, scientists found some nanomaterials showed
enzyme-like activity, and Scrimin and co-workers coined the term
‘‘nanozyme’’ in 2004. In 2007, Yan and co-workers verified the
inherent peroxidase-like activity of Fe3O4 nanoparticles.[2] Since
then, nanozymes have received rising attentions in various fields,
and a large number of nanomaterials with enzyme-like character-
istics have been proposed. Nanozymes are nanomaterials with
enzyme-mimicking characteristics [3], including metals (Au, Ag,
Pt, Pd, Ir, Au@Pt), metal compounds (Fe3O4, CeO2, MnO2, CuS,
MnSe), non-metals (SWNTs, C-dots, fullerene), non-metal com-
pounds (g-C3N4, GO). Nanozymes show the behaviors similar to
natural enzymes, such as catalyzing oxidation of substrates, fol-
lowing the same kinetics, pH- and concentration-dependent pat-
Scheme 1. An illustration of the application of nanozymes in the biological field.
2
Coordination Chemistry Reviews 448 (2021) 214170
terns. Nanozymes can also modulate the reactive oxygen and
nitrogen species (RONS) level in cells. For example, cerium nano-
zymes with RONS-scavenging capability can disproportionate
superoxide anions to H2O2 via SOD mimicking activity, and convert
H2O2 to H2O and O2 via catalase mimicking activity, thereby
achieving anti-immunity, cell protection, and disease prevention
or treatment. Furthermore, some nanozymes offer excellent
RONS-generating ability because of their peroxidase activity and/
or oxidase activity to produce reactive oxygen species (ROS), which
are successfully applied in cancer treatment and sterilization
(Scheme 1). However, earlier reports on the catalytic mechanism
of nanozymes mainly focused on ROS, but rarely focused on the
reactive nitrogen species (RNS).
Compared with natural enzymes, nanozymes have considerable
advantageous characteristics. First, nanozymes are higher in cat-
alytic stability, lower in cost, easy in recovery and storage. Second,
nanozymes are more tolerant to surrounding environment, and can
work in a wider range of pH and temperature. Third, nanozymes
with large surface area are conducive to surface modification. Four,
nanozymes have some excellent properties, such as good stability,
tunable activity, specific environmental responsiveness, and adjus-
W. Yang, X. Yang, L. Zhu et al.
table pore size. Additionally, they can be used as a novel platform
to achieve internalization, circulation, penetration, absorption, and
targeting in tissues or cells for certain disease treatment. Five,
some nanozymes possess unique physicochemical properties, such
as magnetism, photothermal qualities, and photodynamic effect,
which can make their behavior controlled remotely via magnetic
field, laser, ultrasound, and even heat.
In the past decade, with the rapid development of nanotechnol-
ogy and in-depth research, nanozymes have made impressive pro-
gress. In addition to the wide range of biological applications, the
basic research has also made significant progress. Therefore, it is
necessary to review the theory and application of nanozymes. In
this review, we firstly elaborate the origin of nanozyme activity
from the perspectives of enzyme structure and nano effects (vol-
ume effect, quantum size effect, and surface effect), revealing the
cause that nanozymes possess enzyme-like properties and func-
tions. Secondly, we systematically summarize and compare the
catalytic mechanisms, and discuss the reasons for their multiple
enzyme-like activities. Then, this paper comprehensively reviews
the RONS regulation-based biological applications, including anti-
inflammation and cytoprotection, neurological disease therapy,
cancer therapy, sterilization and disinfection. Finally, we discuss
the current challenges and future development of nanozymes.
2. Activity origin of nanozymes
Nanozymes are nanomaterials in essence, but they possess the
properties of both enzymes and surface catalyst. It is a cross pro-
duct of many fields, including biological enzymes, nanomaterials
and surface catalyst. To a certain extent, nanozymes surpass them
with new properties and functions, but do not completely beyond
them in all aspects. In this section, we revealed the activity origin
of nanozymes from the aspects of structure and nano effects. In
addition, the reasons that nanozyme activity can be regulated by
their size, morphology, and external stimulation are discussed.
Nanozymes possess enzyme-mimicking characteristics and
functions. From the perspectives of enzymes (Table 1), enzymes
are majorly proteins produced by living cells with an excellent cat-
alytic performance.[4] They often consist of amino acids, saccha-
rides, metal atoms, and other cofactors.[5] Enzymes generally
have a specific active site, for example, heme molecules coordi-
nated in the protein scaffold serve as the active site in many
peroxide-related enzymes. The center of heme is occupied by
metal atoms like Fe, Cu, Mn, or Zn, which are critical for catalysis
(Fig. 1a, b, c). In addition, they possess a substrate binding site
formed by amino acids with specific structure, which provide the
stereoscopic space for cofactor and metal atom coordination and
substrate binding. This complex but precise structure endows
enzymes with excellent catalytic activity and selectivity.[5] Nano-
zymes are a class of nanomaterials that possess intrinsic enzyme-
Table 1
Comparison of structure and properties between natural enzymes and nanozymes.
Natural enzymes
Essence Majorly proteins
Composition Amino acids, saccharides, metal atoms/ion, and cofactors.
Structure (a) With active site. E.g., metal atoms in heme’s
characteristics center.
(b) Substrate binding site with specific structure.
Number of active sites Limited
Utilization of active High
sites
Catalytic characteristics High catalytic activities and substrate specificity.
3
Coordination Chemistry Reviews 448 (2021) 214170
like properties.[5] Because the size is reduced to nanometer level,
nanomaterials exhibit remarkable physicochemical properties that
are distinctly different from bulk inert materials. Due to many sus-
pended bonds and undercoordination, the atoms on nanomaterial
surface have extra energy and become unstable.[6] These high-
energy surface atoms give nanozymes specific activity to react
with other substances (Fig. 1c, d, e). Particularly, single atom nano-
zymes with enzyme-mimicking structure exhibit superior catalytic
performance. In addition, nanozymes can catalyze bioorthogonal
reactions not addressed by a natural enzyme, which may be due
to their multivalent elements, multiple active sites, or abundant
coordination structures.[7] Surprisingly, grafting chiral amino
acids onto nanoparticle surfaces can indirectly endow them with
a stereoselectivity, in which the functionality of amino acids may
be similar to that of proteins in natural enzymes.[8,9] Yang and
co-workers also obtained chiral carbon quantum dots with enan-
tioselectivity using chiral amino acids as raw materials.[10]
From the aspects of nano effects (volume effect, quantum size
effect, and surface effect). First, in terms of size, nanomaterials
belong to the intermediate domain between atoms and ordinary
particles. Their properties and characteristics are significantly dif-
ferent from those highly active atoms and ordinary particles. When
the size is equivalent to or smaller than some physical characteris-
tics (such as the wavelength of light, the de Broglie wavelength of
conducting electrons, and the coherence length or projection depth
of superconducting state), the periodic boundary conditions of
crystal are destroyed and the atom density near the surface of
amorphous nanoparticles decrease.[13,14] Consequently, their
physical and chemical properties (e.g., light, sound, electricity,
magnetism, chemical activity, and catalysis) changes substantially.
Second, bulk materials possess continuous energy bands. When
particle size reduces to nanometer level, the electronic energy
levels near the Fermi level change from quasi-continuous to dis-
crete energy levels. When the energy level spacing exceeds ther-
mal energy, magnetic energy, electrostatic energy, magnetostatic
energy, photon energy, or superconducting condensed energy,
the quantum effect appears and alters the properties of nanomate-
rials (light, sound, magnetism, heat, electricity, and superconduc-
tivity). The specific heat, magnetic susceptibility, and catalytic
properties of nanoparticles are related to the parity of the con-
tained electrons. [13,14] In a word, the nanoscale size endows
nanomaterials with novel chemical activity and catalysis.
In general, nanozyme activity depends on their size, morphol-
ogy, and external stimulation (e.g., light, sound, and heat). [2,15–
18] In terms of size, the smaller the particle size is, the higher their
activity will be.[2] It can be explained as follows: First, increase of
specific surface area. With a decrease in the size of nanoparticles,
the specific surface area increases significantly. For example, when
the particle size is 10, 5, and 2 nm, their specific surface area is 90,
180, and 450 m2 g
1, respectively. Such a high specific surface area
changes surface atomic number and surface energy, which greatly
Nanozymes
Nanomaterials
Metal or nonmetal atoms/ion.
(a) With active site. E.g., coordination unsaturated surface atoms.
(b) Without specific substrate binding structure, except for chiral
nanozymes.
Multiple
Low, except for single-atom nanozymes.
High catalytic activity, low substrate specificity.
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Fig. 1. Structural comparison of natural enzymes and nanozymes. (a) The three-dimensional X-ray crystal structure of horseradish peroxidase isoenzyme C (the blue
spheres are Ca atoms). [11] (b) The heme iron atom (red sphere) in the heme binding region of horseradish peroxidase isoenzyme C.[11] (c) The active sites of natural
enzymes, nanozymes, and Fe SAEs.[12] (d) Materials and nanomaterials (the illustration is a cross section, red and yellow spheres represent highly active and active atoms,
respectively). (e) The catalytic structure in carbon nanozymes.[5]

affect the catalytic activities of nanoparticles. Second, increase of tion of atomic movement, the saturated atoms closer to the surface
surface atomic number. With the decrease of particle size, the frac- break away from the original bondage to become active atoms. All
tion of surface atoms increases markedly, along with changes in of the above factors may affect the active sites of nanozymes,
the ratio of surface atoms to total atoms. For example, when the resulting in changes of catalytic activity. Active sites generally refer
particle diameter is 10, 2, and 1 nm, the surface atoms account to surface active atoms or sites, which possess high energy because
for 20%, 80%, and 99%, respectively. [14] The rapid increase of sur- of coordination unsaturation and can easily combine with other
face atom ratio changes the properties of nanoparticles. Third, raise atoms, groups, or substances. The common active sites include
of surface energy. The crystal field environment and the binding coordination unsaturated surface atoms and surface defects (e.g.,
energy of surface atoms are different from the internal one. With steps, kinks, adatoms, and vacancies).
a decrease in size, the specific surface area and the surface atomic
number increases, leading to many dangling bonds and unsatu-
3. Enzyme-like properties of nanozymes
rated bonds on surface atoms. [6,19] These surface atoms with high
surface energy are extremely unstable and easily react with other
Until now, many nanomaterials have been discovered with
atoms, groups, or substances, showing significant chemical and
remarkable enzyme-like activities. The types of enzymatic activity
catalytic activity in nanozymes.
mainly include oxidoreductase (e.g., oxidase (OXD), peroxidase
Nanozyme activity is morphology-dependent. Because atom
(POD), catalase (CAT), superoxide dismutase (SOD), and nitrate
coordination environment and dangling bonds are closely related
reductase) and hydrolase (e.g., nuclease, esterase, phosphatase,
to crystal planes. The more saturated the coordination is, the lower
protease, and silicatein),[22] but most of the catalytic mechanisms
the catalytic activity will be, and vice versa. For instance, the coor-
has not been thoroughly studied. Therefore, this section summa-
dination saturation order: (0 0 1) facet > (0 1 0) facets > (1 0 0) facets
rizes the common oxidoreductase activities (Table 2) and partial
> (0 1 0) facets. It has been shown that the glutathione peroxidase-
hydrolase from reaction conditions, catalytic kinetics, and catalytic
like activity of V2O5 nanozymes: only (0 0 1) facet bound
mechanisms. Furthermore, the reasons for their multiple enzyme-
nanowires < large (0 0 1) and minor (0 1 0) facet bound
like activities are discussed from mechanism.
nanosheets < major (0 1 0) and minor (0 0 1) facet bound
nanoflowers < two major (1 0 0), (0 1 0) facet bound nanospheres.
[7,16,20] In addition, certain external factors (e.g., light, sound, 3.1. Peroxidase activity
and heat) may stimulate nanozyme activity due to the activation
of electrons after gaining energy.[21] Taking nanoparticles as an Peroxidase-like activity is the earliest confirmed activity and
example, when given a certain amount of energy, on the one hand, has been discovered in various nanomaterials covering metal,
the coordinated unsaturated atoms on nanoparticle surface will be metal oxide, and carbon nanozymes. Similar with natural peroxi-
excited into more active atoms. On the other hand, with accelera- dase, nanozymes catalyze substrate oxidation with pH-,
4
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Table 2 stances in organisms are considered as substrates of peroxidases,

Comparison of typical catalytic mechanism in nanozyme activity. such as nucleic acids, proteins, polysaccharides, and lipids. There-
Activities Mechanisms Specific Functions Reference fore, substrate oxidation by peroxidase occurs frequently.
POD ROS Catalyzing the production of ROS by [2,23–30] Just as horseradish peroxidase, the peroxidase-like activity of
generation certain reactions (e.g., Fenton, Haber- nanozymes follows the typical Michaelis-Menten kinetics and
Weiss reactions), which can come ping-pong mechanism.[2] It binds and reacts with the first sub-
from both substrates and strate, subsequently releasing the first product before reacting
nanozymes.
Electron Enriching and transferring electron [31–34]
with the second substrate.[31] In general, nanozyme peroxidase-
transfer without producing OH or even like activity has a higher Km for H2O2 and a lower Km for another
inhibiting the production of OH. substrate (TMB) than natural enzymes, indicating that nanozymes
OXD Reactive Producing free radicals or ROS by [35–40] show a higher affinity towards TMB but a lower affinity towards
species activating substrates or dissolved
H2O2.[2] Most of the catalytic efficiency is higher than that of nat-
generation oxygen.
Electron Enriching and transferring electron, [41,42] ural enzymes.[51] The reason may be that nanozymes have a larger
transfer or transferring electron by redox specific surface area and more active sites. However, by contrast,
reaction. the specificity of nanozymes is unsatisfactory due to the lack of
CAT Adsorption Promoting the decomposition of [43] substrate binding sites. Interestingly, the profuse functional groups
activation H2O2 by the high adsorption energy.
in carbon nanozymes provide unexpected functions. The ketonic
Redox Decomposing H2O2 by redox [34,44,45]
reaction reaction. carbonyl, carboxylic, and hydroxyl groups are suggested as the cat-
SOD Adsorption Promoting the disproportionation by [46,47] alytic active centers, substrate binding sites and inhibitors, respec-
activation adsorption. tively.[52] Some researchers have recently improved the substrate
Electron Realizing the disproportionation [45,48,49]
selectivity via molecular imprinting technique or assembly of
transfer reaction by free radical reaction or
redox reaction. amino acid residues on nanozymes. [9,10,53]
In general, the catalytic pathway of peroxidase mimics mainly
consists of ROS generation and the electron transfer process. For
temperature-, and concentration-dependence. They generally have the generation of ROS, nanozymes react with H2O2 to produce
two substrates in the reaction, one is peroxide (mostly H2O2), and ROS (e.g., OH, O2
, HO2), which are responsible for further oxidiz-
the other is oxidized substrate.[5] For certain nanozymes, some ing substrates (Fig. 2a). Fe3O4 nanoparticles are the first proposed
special substances (such as halide, glutathione, thiol, etc.) may be nanozymes with intrinsic peroxidase-like activity, in which the
necessary to complete the entire catalytic reaction.[50] Many sub- surface ferrous ions play a dominant role in activation of H2O2

Fig. 2. The catalytic mechanisms of nanozymes. (a) ROS generation mechanism of the POD-like activity of Cu-CDs-Fe2+.[58] (b) The proposed electron transfer mechanism
for the POD-like activity of Ti3C2 nanosheets.[59] (c) ROS generation mechanism of TiO2/C-QDs as oxidase mimics.[39] (d) The catalytic mechanism of PB with CAT-like
activity.[34] (e) The energy-based model for the activation of 3O2 by metal surfaces.[46] (f) A schematic illustration of chiral CdTe-based specific DNA cleavage under CPL
irradiation.[9]

5
W. Yang, X. Yang, L. Zhu et al.
and generation of ROS via Fenton or Haber-Weiss reactions.[2,23–
27] In MOFs, the Fenton-like mechanism are proposed when H2O2
is absorbed and O-O bond breaks down to produce OH radicals on
nanomaterial surface.[28,29] In addition, although it is also a free
radical mechanism, nanocarbon oxides undergo carboxyl-group-
assisted decomposition of H2O2. The carboxyl groups of nanocar-
bon oxides are oxidized into peroxycarboxyl groups and homolyt-
ically cleaved, generating OH and oxidizing TMB into oxTMB.[30]
For the electron transfer process, the substrates are first
absorbed on nanozyme surface donating electrons. The large speci-
fic surface area with abundant active sites or variable oxidation
states endows nanozymes with an increased electron density and
excellent mobility, thereby resulting in the redox reaction between
substrates and H2O2. The rapid electron transfer from substrates to
H2O2 further accelerates substrate oxidation and H2O2 reduction.
The characteristic of this process is that it does not produce or even
eliminate OH (Fig. 2b). Recently, Qu and co-workers discovered
that electron transfer occurred from the top of graphene valence
band to the lowest unoccupied molecular orbital (LUMO) of
H2O2. In this progress, TMB or other substrate molecules absorbed
on graphene surface and donated the lone-pair electrons in their
amino groups to graphene, resulting in an increased electron den-
sity and mobility on graphene.[31] Another study also demon-
strated that the peroxidase-like activity of Co3O4 NPs was
attributed to the electron transfer between reducing substrates
and H2O2, rather than the production of free radicals.[32,33] Fur-
thermore, the peroxidase-mimicking activity of Prussian blue
nanoparticles could inhibit OH formation, which may be due to
their abundant redox potential as an efficient electron trans-
porter.[34]
3.2. Oxidative activity
Oxidases can catalyze the oxidation of substrates into oxidized
products and H2O/ H2O2/ O2
with the assistance of molecular
oxygen (or other oxidizing reagents).[20] Similarly, nanomaterials
(e.g., Ru, Au@Pt, CeO2, N-CNMs) have been discovered with the
ability of oxidizing substrates, and their catalytic activity strongly
depends on temperature, pH and substrates. The nanozyme activ-
ity also shows typical Michaelis-Menten behavior. [54–57] Most
studies have shown that their Km value are lower than that of nat-
ural enzymes, indicating that the oxidase-like activity displays a
higher affinity toward substrates. In other words, only a low con-
centration of substrates is needed to achieve high catalytic effi-
ciency of nanozymes.
The reaction pathway of nanozyme oxidase-like activity
includes electron transfer and reactive species generation. In elec-
tron transfer process, nanozymes act as the recipient and transfer
of electrons. For the oxidase-mimicking activity of naked gold
nanoparticles (AuNPs), it was considered that the hydrated glucose
anion was first adsorbed onto the gold surface to form electron-
rich gold species, subsequently activating dissolved oxygen by a
nucleophilic attack and generating a dioxo gold intermediate to
transform electrons from glucose to dioxygen.[41] Research
showed that MoO3 exhibited sulfite oxidase activity. The catalytic
mechanism was speculated that SO2- 3 was bonded firstly and oxi-
dized to SO2-4 on MoO3 nanoparticles with variable oxidation states,
along with a reduction of Mo (VI) to Mo (IV). Then, Mo (IV) was oxi-
dized back to Mo (VI) via two one-electron reduction reactions.[42]
For reactive species generation, free radicals originate from
either oxygen molecules or substrates. For the mimicking methane
monooxygenase of trinuclear complex [Cu3(m-O)3]2+, free radicals
are generated from substrates. In this process, methane is activated
first via the interaction of the respective single-occupied molecular
orbital of [Cu3(m-O)3]2+ with the antibonding CH orbital (s*(CH)) of
methane, then the C–H bond is cleaved, resulting in a CH3 and an
6
Coordination Chemistry Reviews 448 (2021) 214170
OH group bonding to the cluster. After CH activation, the barrier-
less recombination of CH3 radicals with Cu-bound OH group in
the cluster forms methanol molecules that preferentially coordi-
nates to two neighboring Cu centers of the trinuclear species.[35]
Some reports identified that free radicals came from activated dis-
solved oxygen. Nanozymes with large specific surface areas could
adsorb and activate massive dissolved oxygen to produce ROS
intermediates (e.g., O2
, 1O2, OH), which were responsible for
substrate oxidation (Fig. 2c). [36–39] Huang and coworkers indi-
cated that O2
was produced first, then subsequently converted
into H2O2 and 1O2 immediately via the oxygen radical chain reac-
tion.[40]
3.3. Catalase activity
H2O2 is an essential ROS in nature. Nanozymes with catalase-
like activity can catalyze H2O2 to generate water and oxygen
molecular. It depends on the concentration of both substrates
and nanozymes, and its decomposition rates become higher with
an increased concentration of them.[60] This process can prevent
the accumulation of ROS, effectively protecting cells from oxidative
stress. The catalase-mimicking activity is generally evaluated by
the level of O2 or dissolved oxygen during the reaction process.
The activity of nanozymes is highly pH- and temperature-
dependent. Most prefers neutral and alkaline environments, but a
few nanozymes also exhibit catalase-like activity in slightly acidic
environment. [32,61] Similar to catalase, it also follows a typical
Michaelis-Menten catalytic process, and nanozymes have a high
affinity for H2O2.[62]
The catalytic reaction by catalase-like activity is closely associ-
ated with nanoparticle morphology, structure, and surface valence,
as well as environmental pH. Currently, the understanding of their
catalytic mechanism of nanozymes is exceedingly limited. Usually,
the catalytic mechanisms include adsorption activation and redox
reactions. With regard to metal-based catalase-mimicking nano-
zymes, the catalytic mechanism was closely associated with free
radical chains. The preabsorbed OH* (* means species adsorbed
on metal surfaces) performed a key role on nanozyme surfaces,
and could prompt H2O2 to prefer acid-like decomposition, then
the decomposed H reacted with pre-adsorbed OH* to yield HO2*
and H2O*. Subsequently, the generated HO2* passed H to another
H2O2*, leaving an O2* and converting the H2O2* to H2O* and OH*.
[43] In addition to free radical reaction, the decomposition process
of H2O2 was accompanied by a redox reaction due to the presence
of redox forms in Co3O4 nanozyme. At a high pH, H2O2 reacted with
OH– to form OOH
, which was more nucleophilic than H2O2 and
could easily interact with Co (III) to generate O2H and Co (II).
The produced O2H would further react with OH that generated
from H2O2 activation by Co (II). A high pH would facilitate the
two reactions, accelerating decomposition of H2O2 by Co3O4.[44]
Similarly, since multiple redox forms and low redox potential of
H2O2/O2 at a high pH, Prussian blue also exhibited an inherent
catalase-like activity (Fig. 2d).[34] Surprisingly, CeO2 as catalase
mimics showed a redox-state-dependent manner. The H2O2 mole-
cules bound to Ce3+ site and their O–O bond split to release water
molecules with the electrons transfer from H2O2 to two Ce3+, then
Ce4+ backed to Ce3+ via oxidation reaction.[45] The high valence
state on nanozyme surfaces is beneficial to their catalase activity.
[61,63]
3.4. Superoxide dismutase activity
Superoxide anions, including HOO and O2
(O2
is the main
form), are destructive ROS widely distributed in cells. They can ini-
tiate a radical-chain reaction producing more toxic free radicals. In
general, superoxide anions can self-decay in natural conditions,
W. Yang, X. Yang, L. Zhu et al.
but the decay rate is exceedingly slow. Hence, superoxide dismu-
tase is an important antioxidant that responsible for the dispropor-
tionation of superoxide anions into H2O2 and O2. Benefiting from
the scavenging capacity of O2
, nanozymes (e.g., Pd, MnO2, PB,
fullerene) are considered as promising alternatives to superoxide
dismutase. When nanozymes possess multiple enzyme activities,
the environmental pH or the structure and surface ions of nanoma-
terials make superoxide dismutase activity become the dominant
activity. Inappropriate pH leads to a thicker electrostatic barrier
to superoxide radicals, suppressing the catalytic activity.[47] Sim-
ilar with natural enzymes, the kinetics follow a ping-pong
mechanism.
Due to the unpaired electrons and multivalent ions on surface,
the primarily contributions of nanozymes are adsorption activa-
tion and electron transfer. However, the actual mechanisms are
determined by pH, nanozyme structures, or surface ions. For the
superoxide dismutase-like activities of metal and alloy, the mech-
anisms mainly include the protonation of O2
and the adsorption
and rearrangement of HO2 on metal surfaces. O2
is a Brønsted
base that easily captures a proton from water to form HO2 and
OH
, and this process is accelerated due to the strong adsorption
of HO2 on nanozyme surface. Consequently, the rearrangement
of HO2* occurs with the formation of H2O2* and O2* (Fig. 2e).
[46] Reports showed that C60[C(COOH)2]3 nanozymes (C3) could
remove superoxide radicals via the attraction of electron-
deficient regions. C3 electrostatically drove superoxide anions
toward electron-deficient areas on its surface, then O2
was stabi-
lized via the hydrogen bonding and protons of carboxyl groups (or
intercalated solvating H2O) until the second O2
arriving to com-
bine with the original O2
. It allowed O2
dismutation with the
assistance of protons from carboxyl groups or local water mole-
cules.[47] Due to the presence of many unpaired electrons and
the planar structure accepting electrons from O2
, poly-
(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) offered
superior superoxide dismutase-like activity, but was inert to nitric
oxide (NO) and peroxynitrite (ONOO
).[48] Unlike above nano-
zymes, melanin nanoparticles (MeNPs) with superoxide
dismutase-like activity could scavenge O2
, NO and ONOO

simultaneously.[49] Nanoceria was one of the first reported nano-
materials that exhibited superoxide dismutase-mimicking activi-
ties, which were ascribed to convertible valence state (Ce3+ and
Ce4+) and oxygen vacancies. Oxygen vacancy could combine with
superoxide, transferring electron via the generation of H2O2, while
the Ce4+ could switch back to the original Ce3+ through the oxida-
tion of H2O2.[45]
3.5. Hydrolase
Hydrolase, one of common enzyme activities, plays a vital role
in biological systems by catalyzing hydrolysis of chemical bond.
Emerging studies have discovered that various nanomaterials
(such as Au, CeO2, Ce-AuNPs, MOFs, Fe3O4, ZrO2) exhibit excellent
hydrolase-like activity.
Although minimal studies involve the catalytic mechanism of
hydrolase-like activity in nanozymes, bond breakage is closely
related to free radicals. As previously reports, MOF/g-C3N4 displays
hydrolases-like activity towards dimethyl chlorophosphate (DMCP)
via two steps, namely adsorption and decomposition of substrates.
First, the vaporized DMCP molecules are adsorbed through the
complexation of DMCP molecule on copper sites by its P=O group,
then there are specific interactions between DMCP and copper-
based amorphous phase, including the formation of hydrogen
bonds or the polar interactions between P=O group and hydroxyl
groups of uncoordinated BTC units or positively charged Cu2+,
respectively. Second, the chlorine atom of DMCP is replaced by
hydroxyl group in water molecules, and DMCP is hydrolyzed to
7
Coordination Chemistry Reviews 448 (2021) 214170
DMP.[64] Kuang and co-workers [9] also discovered that chiral
cysteine-modified CdTe nanoparticles could mimic restriction
endonuclease to specifically recognize and cut at the restriction site
GAT0 ATC in double-stranded DNA exceeding 90 base pairs (Fig. 2f).
During this process, nanoparticles acted as electron donors to
induce ROS generation, while DNA was an electron acceptor to
cleave phosphodiester bond. In their another study,[65] chiral cop-
per sulfide quantum dots (d/l-QDs) were used as photocatalysts to
cleave proteins. The OH produced by d/l-QDs caused the cleavage
of peptide bond between amino acids K and L, resulting in the cleav-
age of proteins at specific sites (61 KD + 5KD).
3.6. Diversity of nanozyme activity
The most significant feature of nanozymes is their multiple
enzyme-like activities. Although different nanomaterials have the
same catalytic activities, their catalytic mechanisms are com-
pletely depending on environmental pH, or size, surface ions states,
and morphology of nanomaterials.
Nanozymes possess multiple enzyme-mimicking characteris-
tics and catalytic mechanisms at different pH. (1) For noble metal
nanozymes (e.g., Au, Ag, Pt, and Pd), the peroxidase activity is pre-
sented at pH 4.5 to catalyze H2O2 into OH radicals, while the
catalase-mimicking activity is presented at pH 7.4 to decompose
H2O2 into O2. Through density functional theory calculation, Gao
and co-workers [43] contended that pH-dependent behavior was
mainly attributed to two different decomposition pathways of
H2O2 caused by preabsorbed H+ or OH
on nanozyme surface
(Fig. 3a). Under acidic conditions, H* was pre-adsorbed on nano-
zyme surface, which had little influence for the adsorption and
decomposition of H2O2. H2O2 preferred base-like decomposition
pathway, making O
O bond broken into two OH* followed by
the formation of H2O* and O*. After O* further attacked organic
substrates (e.g., TMB) to obtain H atoms, the catalytic process of
noble metal nanozymes was completed. Under base conditions,
OH* was pre-adsorbed on nanozyme surface, resulting in the
acid-like decomposition pathway of H2O2. The O–H bond of
H2O2* broke and transferred a H to OH generating HO2* and
H2O*. The latter would quickly transferred one H to another
H2O2, forming O2*、H2O* and OH*. (2) For iron oxide nanozymes
(IONzymes), in acidic conditions, IONPs with peroxidase-like activ-
ity catalyze H2O2 into OH by Fenton or Haber-Weiss reaction.
However, in neutral and alkaline conditions, IONzymes directly
decompose H2O2 into H2O and O2 due to the catalase-like activity.
Research showed that the multiple enzyme-like behaviors of ION-
zymes were mainly owned to redox potential of H2O2 in different
pH environments, while H2O2 activation and free radical genera-
tion were closely associated with the reversible redox of iron ion.
Since electrons were transferred from a low potential to the high
one, Fe3+/Fe2+ (0.771 V) could not transfer electrons from TMB
(TMBOx /TMBRe 1.13 V) to H2O2 (1.776 V) in low pH environment.
When in the high pH environment, H2O2 was directly decomposed
due to the reduced redox potential (0.695 V).[24] (3) Prussian blue
(PB) nanozymes, one of iron-based nanozymes, are alternately con-
nected by Fe2+–CN–Fe3+ to form cyanide-bridged cubic networks.
[7] Unlike IONPs, PB was found with the ability of scavenging ROS
[34]. Due to various redox potentials and adjustable energy levels,
Prussian blue served as efficient electron transporters and pos-
sessed pH-dependent enzyme-like activity. At the acidic environ-
ment, high activity H2O2 oxidized Prussian blue (PY/BG: 1.4 V) by
transferring electrons from TMB (TMBOx /TMBRe 1.13 V) to H2O2
(H2O2 /H2O 1.776 V), contributing to the peroxidase activity of
Prussian blue. When in the high pH environment, the redox poten-
tial of H2O2/ O2 was exceedingly low, making H2O2 more easily oxi-
dized into O2. In this case, fewer PB were oxidized into BG or PY to
transfer electrons from TMB to H2O2. Hence, Prussian blue exhib-
W. Yang, X. Yang, L. Zhu et al.
Fig. 3. The multi-enzyme activities of nanozymes. (a-c) The pH-depended multi-enzyme activities of noble metal nanozymes (a)[7], Prussian blue (b)[34], and Co3O4 (c)[7].
(d) The multi-enzyme activities of CeO2 depend on the size, surface ion, and morphology.[18]
ited catalase-like activity. Interestingly, because H2O2 could be
transformed into H2O or O2 by the POD- or CAT-like activity, Prus-
sian blue were capable of catalyzing dismutation of O2
due to the
presence of O2/O2
(0.73 V) and O2
/H2O2 (1.5 V). Therefore, Prus-
sian blue could mimic superoxide dismutase at different pH levels
(including acidic and alkaline) (Fig. 3b). (4) Co3O4 also exhibits pH-
dependent enzyme-mimicking activities due to high redox poten-
tial of Co3+/CO2+ (1.3 V). The mechanism is similar to that of Prus-
sian blue. Under acidic condition, Co3O4 can transfer the lone pair
electrons of amino group from TMB to H2O2. The increased electron
density and flow rate on nanozymes accelerate electron transfer
process, which is attributed to the peroxidase-like activity. How-
ever, under neutral /alkaline conditions, the oxidation ability of
Co3O4 is very high, thus Co3+ directly oxidizes H2O2. This is the cat-
alytic behaviors of CAT and SOD in Co3O4, and its CAT activity is
much higher than that of IONzymes (Fig. 3c). [32,33]
The multiple enzymatic behaviors in nanozymes are also closely
related to their size, surface ions, and morphology. For example,
the catalytic activities of CeO2 depend on surface ions and size.
In the fluorite structure of CeO2, each cerium atom is surrounded
by eight oxygen anions, and each oxygen atom occupies a tetrahe-
dral position. Many inherent oxygen holes usually exist in this
structure, producing Ce3+.[66] Therefore, there are two valence
ions and a special redox cycle (Ce3+/Ce4+) on CeO2 surface. Smaller
CeO2 possessed more Ce3+ and oxygen vacancy at their surface,
which facilitated the SOD activity. On the contrary, large sized
CeO2 was conducive to CAT activity. [15,45,63,67,68] In addition,
the catalytic activity of CeO2 also depends on morphology. Wu
and co-workers [17] stated that the peroxidase activity of nano-
cube (1 0 0) plane was much higher than that of nanorod (1 0 0)
plane, but the superoxide dismutase activity of nanocube was
much lower than that of the nanorod. The exposed surface of
CeO2 was related to Ce3+/Ce4+ concentration. CeO2 nanopolyhe-
drons with (1 1 1) and (1 0 0) ((1 1 1)> (1 0 0)) contained a higher
Ce4+ concentration, which was beneficial to superoxide dismutase
activity (Fig. 3d).[18]
8
Coordination Chemistry Reviews 448 (2021) 214170
4. Biological applications of nanozymes
Reactive oxygen and nitrogen species (RONS) play an essential
role in cell proliferation, migration, differentiation, signal transduc-
tion, tissue homeostasis, and immunity, as well as the defense
against pathogenic invasion.[1,69] However, excessive active spe-
cies will cause a series of diseases, such as stroke, sepsis, diabetes,
hypertension, neurodegenerative diseases, inflammation, and can-
cer.[69] Under normal physiological conditions, intracellular RONS
level is modulated by antioxidant enzymes and some small-
molecule antioxidants.[1,70,71] Due to the intrinsic enzyme-
mimicking characteristics, nanozymes can participate in RONS
removal of body. In addition, because of the excellent RONS pro-
duction capacity, nanozymes can be applied in cancer therapy,
sterilization, and disinfection. Based on above, this section will
comprehensively summarize the biological applications of nano-
zymes, including anti-inflammatory and cytoprotection, neurolog-
ical disease therapy, cancer therapy, sterilization and disinfection.
4.1. Anti-inflammatory and cytoprotection
ROS are the products of normal cell metabolism in organisms,
but ROS in excess will give rise to cellular oxidative stress, affecting
its normal growth, metabolism, and basic functions. [72–74] A
variety of nanozymes possess antioxidant properties, which can
regulate ROS levels to protect cells and promote growth. Cerium
nanoparticles are one of the nanozymes with antioxidant activity.
According to Singh’s reports [75], low dose Cerium nanoparticles
effectively scavenged free radicals in human liver cells without
eliciting natural antioxidant defense system, and prevented cells
from early apoptosis and DNA damage. Another study also
reported a similar result that the mice treated with ceria had a sub-
stantial decreased ROS level and significantly reduced damage in
tissue and DNA.[76] Interestingly, by functionally mimicking the
antioxidant enzyme glutathione peroxidase, V2O5 nanowires also
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Fig. 4. The applications based on RONS removal of nanozymes. (a) Schematic diagram depicting the GPx-like antioxidant activity of vanadia nanowires and GSH recycling
by GR for cytoprotection; and (b) The scavenging ability of V2O5 nanowires for extrinsic H2O2 and intrinsic cellular peroxide induced by CuSO4 was measured by using
genetically encoded H2O2-specific probe HyPer in HEK293T cells.[50] (c) Preparation process of CeRMS; (d) Neural differentiation of neural stem cells after treating with
different nanoparticles for 10 days (Scale bar: 50 lm); and (e) Representative swimming path in cognitive function of 3  Tg-AD mice.[85]

exhibited robust antioxidant activity to scavenge the reactive oxy-
gen species in physiologically conditions (Fig. 4 a, b). After being
internalized into cells, V2O5 nanowires fully restored the redox bal-
ance, alleviating the oxidative stress in cells without disturbing the
cellular antioxidant defense. Furthermore, V2O5 nanowires pre-
vented oxidative damage of cellular components (such as lipids,
proteins, and DNA), providing crucial cytoprotection for biomole-
cules.[50] NACu-Cys nanozymes with superoxide dismutase
mimetic activity could also eliminate O2
, acting as a protective
agent against oxidative stress. Adding NACu-Cys into human
sperm freezing medium, would raise cell motility and viability as
well as reduce its apoptosis.[77] Compared with natural superox-
ide dismutase, the NACu-Cys nanozymes showed better cell pro-
tection ability.
ROS in excess generally cause uncontrollable inflammation that
is the underlying pathogenesis of most diseases.[78] Nanozymes
with ROS scavenging ability can alleviate inflammation and avoid
associated diseases emerging.[79] Inorganic nanomaterials are
always utilized in photoacoustic or computed tomography con-
trasts to evaluate the diagnosis and treatment of disease, but their
long-term retention in the body usually increases ROS level, lead-
ing to inflammation. To avoid it, bovine serum albumin-iridium
oxide nanoparticles were used to catalyze the production of oxy-
gen due to the inherent catalase-mimicking activity, which not
only enhanced imaging effect but also protected normal tissues
against H2O2-induced inflammation.[80] It was also reported that
CeO2 possessed ROS scavenging capability due to the superoxide
dismutase- and catalase- mimicking activities. The anti-
inflammatory effect of CeO2 was studied by enclosing different
shaped ceria on titanium surfaces for peri-implantitis prevention.
[81] Consequently, nanotube and nano-octahedron CeO2-
modified titanium exhibited a satisfactory anti-inflammatory
effects and ROS-scavenging ability in vitro, while nano-
octahedron CeO2 showed stronger anti-inflammatory effect
in vivo. In addition, CeO2 grown on montmorillonite surface could
effectively reduce the inflammatory reaction by scavenging ROS
(O2
, H2O2, OH), decreasing pro-inflammatory cytokines, and
increasing anti-inflammatory cytokines.[82] Due to the presence
of double oxidation states (Mn2+ and Mn3+), Mn3O4 nanoparticles
also exhibited various enzyme-mimicking activities (i.e., superox-
ide dismutase and catalase), endowing them with O2
and OH
scavenging ability. [83] By contrast, they were more stable than
corresponding natural enzymes and superior to CeO2 nanozymes
in ROS elimination. Moreover, the Mn3O4 nanoparticles exhibited
excellent ROS removal efficacy in vitro, and were able to effectively
protect the mice from ROS-induced ear-inflammation. Most of
anti-inflammatory nanozymes mainly have the ability of ROS scav-
enging, while the RNS scavenging capability is relatively weak. Cao
and co-workers [84] presented a polyethylene glycol-coated ultra-
small rhodium nanodots (Rh-PEG NDs) that showed unexpected
reactive oxygen and nitrogen species (RONS) scavenging properties
and photothermal activities, which could be utilized in an anti-
inflammation in colon diseases. They found that Rh-PEG NDs
decreased the level of pro-inflammatory cytokines (TNF-a, and

9
W. Yang, X. Yang, L. Zhu et al.
IL-6) because of their multiple enzyme-like activities against RONS,
resulting in an excellent anti-inflammatory effect on dextran sul-
fate sodium induced colitis.
4.2. Neurological disease therapy
ROS can cause the dysfunction of proteins and mitochondria,
inducing neuronal damage and neurological diseases. Many natu-
ral enzymes have been applied in the treatment of neurological
diseases. However, the efficacy cannot last long due to the
immunogenicity and limited electron-donating ability in vivo.
[86,87] Nanozymes with intrinsic antioxidant enzyme properties
and excellent biocompatibility have a high potential to be used
in neurological diseases, such as Alzheimer’s disease, ischemic
stroke, brain injury, and so on. Qu and co-workers [88] first pre-
sented a polyoxometalate-based multifunctional nanozyme for
Alzheimer’s disease treatment. The protease-like activity was used
to deplete amyloid-beta (Ab) aggregates, and superoxide
dismutase-like activity for scavenging ROS-mediated Ab. Further-
more, the nanozymes with low toxicity was able to cross blood–
brain barrier. Since neuron loss often occurs in Alzheimer’s disease,
neuron-directional differentiation and neural stem cell niche com-
ponent majorization are often utilized to promote nerve growth,
but their effects are vulnerable to high oxidative stress levels. A
MOF-encapsulated nanozyme was designed for the modulation of
neuron-directional differentiation and the amelioration of oxida-
tive stress (Fig. 4 c, d, e).[85] In the lesion area, the hydrogen
peroxide-responsive MOF released cargos to promote neuron-
directional differentiation, while the integrated ceria eliminated
ROS and averted oxidative damage, resulting in a higher survival
rate and enhanced outgrowth of newborn neurons. Microglia are
resident myeloid cells in the central nervous system, and it partic-
ipates in normal central nervous system functions. Elevated ROS
levels convert M2 microglia into M1 microglia, inducing neurode-
generative diseases and Alzheimer’s disease. Hu and co-workers
[89] designed TPP-MoS2 QDs to scavenge ROS and target mito-
chondria of microglia. Their results proved that TPP-MoS2 QDs
could effectively crosse blood–brain barrier, target mitochondria,
convert microglia, and mitigate Ab-mediated neurotoxicity,
inhibiting neuroinflammation and treating Alzheimer’s disease of
mice.
Nitrogen species (RNS) are common intermediate products of
many neurological diseases, affecting normal metabolism and
functions of nerve cells. Melanin is known as a potential radical
scavenger in most organisms. Lu and co-workers developed mela-
nin nanoparticles with RONS scavenging capacity for the first time.
[49] They found that melanin nanoparticles possessed unique
multi-antioxidative, anti-inflammatory, and biocompatible fea-
tures. Melanin nanoparticles could attenuate RONS-triggered
inflammatory responses by suppressing the expression of inflam-
matory mediators and cytokines, effectively protecting ischemic
brains with negligible side effects in vitro and in vivo. Due to the
variable valence state and extraordinary redox capability, as well
as the unique hollow structure and a large specific surface area,
Prussian blue nanozymes also showed excellent RONS scavenging
capacity for neuroprotection against ischemic stroke.[90] Experi-
mental results indicated that Prussian blue nanozymes effectively
protected neurons against the hypoxic and ischemic injury with
negligible side effects. Based on the ultrahigh RNS selectivity and
catalytic activity of nanozymes, ultrasmall fluorescent carbogenic
was reported.[91] This nanozymes with remarkable RNS / ROS
scavenging efficiency was able to remove harmful peroxide and
superoxide in vivo, reducing immune responses in traumatic brain
injury mice. Unlike conventional inorganic nanozymes, the nano-
zymes exhibited efficient renal clearance without any side effects
at high doses. In another study, a new trimetallic nanozyme was
10
Coordination Chemistry Reviews 448 (2021) 214170
prepared for fast electron capture. In neutral environment, it
attracted and removed RONS radicals, promoting brain injury
treatment.[92] Nanozymes have offered many distinct advantages
in neurological diseases treatment, but the biological safety needs
to be evaluated in the future.
4.3. Cancer therapy
Cancer is one of the most serious diseases threatening human
health, and is often featured with vascular abnormalities, glucose
deprivation, mild acidity, hypoxia, hydrogen peroxide overexpres-
sion, and inflammation. [93–95] The traditional treatments include
surgery, chemotherapy, and radiotherapy, but they usually suffer
from unsatisfactory therapeutic outcome or even are harmful to
the function of normal cells because of postoperative infection,
hypoxia, and the non-targeting effect. Amazingly, nanozymes can
offer many excellent characteristics, including responsive
enzyme-like activities, as well as light, thermal and magnetic
effects, which facilitated ROS generation or removal, oxygen gener-
ation, and remote-control capability. Nanozymes, overcoming the
shortcomings of traditional methods, have been successfully
applied in many cancer treatment strategies (Table 3), including
photodynamic therapy, sonodynamic therapy, chemodynamic
therapy, hyperthermia, photothermal therapy, radiotherapy, cat-
alytic therapy, oxidative therapy, immunotherapy, starvation ther-
apy, and combination therapy.
Numerous nanomaterials can be recognized as photosensitizers,
sonosensitizers, or heat conversion mediums to promote ROS pro-
duction. Owning to the malignant invasiveness, low toxicity, high
selectivity, and enhanced therapeutic effect, nanozymes-based
photodynamic, photothermal and sonodynamic therapy have
become potential anticancer strategy. Recently, the well-defined
single-atom nanozymes (OxgeMCC-r SAE) as a versatile photody-
namic were fabricated, which could decompose endogenous
hydrogen peroxide to generate oxygen continuously due to the
catalase-like activities, thereby overcoming tumor hypoxia for
photodynamic therapy.[96] Under NIR irradiation, high cytotoxic
singlet oxygen (1O2) species were produced, which further
enhanced the therapeutic effect of photodynamic therapy in solid
tumor. In addition, the enzyme-like activities of carbon-based
nanomaterials and AuNPs can be significantly enhanced, resulting
in the generation of high ROS levels. Based on this, Han and co-
workers [97] designed a nanozyme by encapsulating AuNPs within
a hollow porous carbon nanosphere (Au@HCNs). Under 808 nm
light irradiation, the nanozymes showed considerable photother-
mal effect. However, photo-based therapeutic models are only
suitable for treating superficial and localized cancer due to the lim-
ited penetrating depth. By contrast, sonodynamic therapy, another
noninvasive treatment mode, provides great opportunities for can-
cer treatment, in terms of tissue penetrating capability, conve-
nience, and low cost. However, the low quantum yield and
tumor hypoxia hinder the comprehensive applications of sonody-
namic therapy. Cheng and co-workers [98] reported a novel TiO2-
based nanosonosensitizer, which bilaterally enhanced the quan-
tum yield and alleviated tumor hypoxia, faciliting the chemo-
sonodynamic synergistic efficacy. In this Pt-TiO2 heterostructure,
TiO2 servesed as a load reservoir of doxorubicin (an chemotherapy
drug and a sonosensitizer SDT), while the decorated Pt NPs cat-
alyze endogenous hydrogen peroxide decomposition to provide
sufficient oxygen for chemo-sonodynamic synergistic efficacy. Sur-
prisingly, the synergistic effect of chemotherapy and dynamic
acoustic therapy displayed an excellent inhibitive effect on tumor
growth.
Chemodynamic therapy, a typical nanocatalytic therapy strat-
egy, employs Fenton or Fenton-like reactions to convert hydrogen
peroxide into oxidative OH. Tumor site-specific endogenous
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Table 3
Summary of nanozymes for cancer therapy.

Therapeutic Nanomedicine Function Mechanisms Reference

modality
Radiotherapy MnTCPP-Hf-FA MOF As CAT mimics and radiosensitizer Produce O2 to overcome tumor hypoxia [105]
Ir@liposome As CAT mimics and photothermal reagent Generate O2 to relieve tumor hypoxia [106]
Porous PtNPs As CAT mimics and radiosensitizer Generate O2 to alleviate tumor hypoxia [107]
Chemodynamic FePt-NP2 As Fenton reagent Catalyze the production of OH [104]
therapy Co-Fc@GOx As Fenton reagent Generate OH [100]
MnO2@PtCo As CAT and OXD mimics Catalytic the generation of O2 and ROS [101]
Photochemotherapy UCSRF As Fenton reagent and upconversion nanoparticles NIR light-upconverted UV/vis light, and produce [108]
abundant ROS
Photodynamic Au@ZIF-8 As CAT mimics Catalyze the production of O2 and 1O2 [109]
therapy OxgeMCC-r As CAT mimics For continuous oxygen generation [96]
PCN-224-Pt As CAT mimics and photosensitizer Catalyze the formation of O2 and 1O2 [110]
Lipo-Ogzyme-AIE As CAT mimics Supply oxygen for ROS generation [111]
Hyperthermia magnetic hydrogel As POD mimics Generate OH via Fenton reaction [112]
Au@HCNs As POD, OXD, and photothermal reagent For ROS generation [97]
Catalytic therapy DMSN-Au-Fe3O4-PEG As glucose oxidase and POD mimics Generate H2O2 and OH [93]
GSF@AuNPs As POD mimics Catalyzed H2O2 to form OH [113]
N-PCNSs As OXD, POD, CAT and SOD mimics Boost ROS generation [114]
GOx-Fe3O4@DMSNs As Fenton reagent Generate a considerable amount of OH [115]
FePOs As POD mimics Catalyze OH generation to anti-tumor [116]
PtAu@SiO2 As OXD and POD mimics Catalyze the production of O2 and ROS [117]
Combination PEG/Ce-Bi@DMSN As POD, CAT mimics, and photothermal reagent, Produce O2 and OH, whiling depleting GSH to [118]
therapy with GSH-depletion capability weaken tumor’s reducibility
AuNBPs@MoS2 As POD mimics and photothermal reagent Generate ROS (1O2 and OH) [119]
H-Pt-TiO2-DOX As CAT mimics and sonosensitizer Generate O2 and ROS [98]
GOx/hPB@gellan As CAT mimics and photothermal agent Convert H2O2 into O2 [120]
PtFe@Fe3O4 As POD, CAT, and photothermal agent Generate O2 and ROS (1O2 and OH) [121]
PtCu3-PEG nanocages As POD, GSH peroxidase, and sonosensitizer Generate ROS and reduce ROS clearance via [122]
accelerate GSH depletion
HMPB@GOx As SOD, CAT, POD, OXD, and photothermal agent Catalyze the production of H2O2, O2, and ROS [123]
(OH and 1O2)
HMON-Au-Col@Cu-TA- As glucose oxidase, Fenton reagent, and Self-supply H2O2 and convert into OH [99]
PVP photosensitizer
ABTS@MIL-100/PVP As POD mimics and photothermal agent Produce OH and reduce GSH level [124]
rMGB As CAT mimics Catalyze the production of O2 and ROS [125]
Pt-CuS-P-TAPP As CAT mimics and photothermal agent Generate O2 to overcome hypoxia [126]
Pt@UiO-66-NH2@Aushell- As CAT mimics and photothermal agent Decompose H2O2 to supply O2 [127]
Ce6
Au2Pt-PEG-Ce6 As CAT, POD, photothermal agent, and Generate O2 and OH [62]
sonosensitizer
SnFe2O4 As CAT, GSH peroxidase, Fenton reagent, and Produce O2 and ROS, consume GSH to relieve [128]
photothermal agent antioxidant capability
IrOx-Gox As POD, OXD, and CAT mimics Supply O2 and ROS, and consume GSH [129]
IrRu-GOx@PEG NPs As POD and CAT mimics Convert H2O2 into 1O2 and O2 [130]
Au/Pt star@S-S@ As POD mimics and photothermal reagent Catalyze H2O2 to produce toxic OH [102]
rHSAFA@IR780 @GOx
IMSN-PEG-TI As POD and CAT mimics Decompose H2O2 into OH and O2 [61]
CaO2/DOX@SiO2/DOX– As CAT mimics Generate H2O2 and O2 [131]
MnO2 NR
MON-p53 As Fenton reagent Produce ROS to cause lipid peroxidation [103]

chemical energy is exploited to produce OH, protecting normal tis-
sues from oxidative damage without external energy input. [93,99]
For instance, Co-Fc NMOF not only exhibited an excellent Fenton
effect, but also acted as a versatile delivery medium of glucose oxi-
dase (GOx) molecules. After glucose oxidase was delivered into
tumor and endogenous glucose was catalyzed to form hydrogen
peroxide, Co-Fc@GOx dramatically amplified the induction of cyto-
toxic OH in situ, enhancing the inhibition effect against cancer
cells.[100] Furthermore, the catalase-like activity of MnO2 could
rapidly decompose hydrogen peroxide into oxygen to address
tumor hypoxic, while the oxidase-mimicking behavior of PtCo cat-
alyzed oxidation reaction to generate ROS. As a result, MnO2@PtCo
nanoflowers induced significant cell apoptosis via the ROS-
mediated mechanism, resulting in remarkable and specific tumor
growth inhibition.[101] However, the therapeutic outcomes of
nanozyme-based tumor catalytic therapy are diminished due to
many factors in tumor microenvironment (TME), including insuffi-
cient endogenous hydrogen peroxide concentration, hypoxia, and
immunosuppressive microenvironment. In view of this, Liu and
Wei [61] proposed an immunomodulation-enhanced nanozyme-
based tumor catalytic therapy strategy, in which iron manganese
silicate nanoparticles (IMSN) with POD- and CAT-like activities
decomposed hydrogen peroxide into OH and O2 under acidic
TME, while TGF-b inhibitor (TI) regulated tumor immune microen-
vironment to induce the regeneration of hydrogen peroxide, pro-
moting the catalytic activities of IMSN nanozymes (Fig. 5 a, b, c).
The related results suggested that the synergism effect of nano-
zymes and TME regulation could achieve a more optimistic thera-
peutic effect. In most cases, due to the complex tumor
microenvironment, it is generally difficult to achieve desired effect
by single treatment strategy. Therefore, synergistic therapy strate-
gies often attract more attentions. Recently, Au/Pt star@S-S@rHSA-
FA@IR780@GOx was reported, in which iodide diagnostic probe
(IR780) for real-time imaging, photothermal reagent (Au) for pho-
tothermal therapy, photosensitizer (IR780) for photodynamic ther-
apy, glucose consuming enzyme (GOx) for starvation therapy, and
peroxidase-mimicking ability (Pt) for oxidative therapy. Once the
disulfide linker was cleaved by GSH in tumor sites, IR780 were

11
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Fig. 5. The applications based on RONS generation of nanozymes. (a) Schematic illustration of synthesis and tumor therapy for IMSN-PEG-TI; (b) Tumor volume of CT26-
tumor-bearing mice after different treatments at 15 days; and (c) Survival of CT26-tumor-bearing mice after different treatments.[61] (d) Schematic illustrating PCN-224-Ag-
HA nanoagents with surface adaptive characteristic for on-demand synergistic bacteria killing; (e) Photographs of MRSA-infected wounds on mice in each group with
different treatments during on the third day; and (f) The bacteria separated from wound tissue after different treatments were cultured on agar plates.[132]

released and GOx catalyzed intracellular glucose to generate
hydrogen peroxide, enhancing the local acidity. The Pt layer with
peroxidase-like properties catalyzed hydrogen peroxide to produce
toxic OH for tumor oxidative damage. Consequently, it could
simultaneously realize real-time imaging and synergetic cancer
treatment via starving-like therapy/enzyme oxidative therapy/
photothermal therapy/photodynamic therapy.[102] Compared
with the single treatment strategy, combination therapy is more
effective and more likely to achieve successful cancer treatment
in the future.
Cancer cells proliferate rapidly, whereas the ROS generated by
nanozymes causes oxidative damage to lipids, proteins, and DNA
in the cancer cells, affecting their basic biological functions or even
leading to death.[103] As reported, Metal-organic network (MON)
encapsulated with p53 plasmid (MON-p53) eradicated cancer cells
via the ferroptosis/apoptosis hybrid pathway by harnessing the
oxidative stress regulation ability of p53 and the Fenton
reaction-inducing capability of metal–organic network.[104] The
ferric ions in p53 plasmid catalyzed the overexpressed hydrogen
peroxide to form ROS in the tumor environment, causing serious
lipid peroxidation of biofilm. Furthermore, p53 genes encapsulated
in p53 plasmid was released, inducing the expression of p53 pro-
tein, further inhibiting lipid peroxide elimination and sensitizing
cells to ferroptosis. A 75-day anti-cancer experiment treatment
confirmed this treatment strategy.
4.4. Sterilization and disinfection
Bacterial infection often causes significant morbidity and mor-
tality, which has become one of the substantial health challenges.
H2O2 is widely used for bacterial inactivation and wound disinfec-
tion. However, its dosage exceeds physiological levels, often caus-
ing potential toxicity to healthy tissue or even delaying wound
healing.[133] Numerous nanozymes as powerful sterilization tools
have been developed due to their excellent ROS production capac-
ity. For instance, Au/g-C3N4 hybrid nanozymes displayed strong
peroxidase-like activity, which could efficiently catalyze biologi-
cally relevant concentrations of H2O2 decompose into OH radicals,
showing great potential in preventing bacterial infection. By break-
ing down drug-resistant-biofilms and preventing new biofilm for-
mation, the hybrid nanozymes possessed remarkable bactericidal
ability against both drug-resistant Gram-negative and Gram-
positive bacteria. Particularly, the hybrid nanozymes could signifi-
cantly prevent bacterial infections and accelerate wound healing at
lower H2O2 concentration. [133] According to the report, MOF/Ce-
based nanozymes are also conducive to sterilization due to the
deoxyribonuclease- and peroxidase- mimicking activities.[134]
The nanozymes not only killed bacteria via ROS, but also hydro-
lyzed extracellular DNA, disrupting the established biofilms and
avoiding bacteria recolonization and biofilm recurrence. In addi-
tion, metal ion release from metallic-based nanozymes is also a
favorable condition for sterilization. It was shown that the released
Cu2+ from CuO-modified copper/carbon nanozymes caused mem-
brane damage, lipid peroxidation, and DNA degradation in Gram-
negative bacteria.[135] Ag ions was also a potential antibacterial
material, in order to eliminate their toxic effect, a novel antimicro-
bial nanoplatform was fabricated by combining hyaluronic acid
protected Ag ions with metal–organic frameworks (Fig. 5 d, e, f).
[132] Owing to the released Ag ions and generated reactive oxygen
species, the nanoplatform provided a synergistic antibacterial
effect and showed good biocompatibility with nontargeted cells.
For ROS-based sterilization, effective capture and reaction of bacte-
ria by nanozymes are prerequisites for efficient sterilization,
because the intrinsical lifetime (shorter than 200 ns) and diffusion
distance (approximately 20 nm) of ROS are limited. Wang and co-
workers [136] provided an antibacterial nanozyme (Cu2WS4

12
W. Yang, X. Yang, L. Zhu et al.
nanocrystals, CWS NCs), it first effectively adsorbed bacteria via
the interaction between copper atoms of CWS NCs and amino
groups from peptidoglycan of bacterial cell wall. Then bacteria
were killed by ROS produced by nanozyme oxidase-like and
peroxidase-like activities. Consequently, the CWS NCs with a low
dose achieved > 99.999 % inactivation against both Gram-
negative and Gram-positive bacteria, which was far superior to
typical antibacterial nanomaterials (Ag and TiO2 nanoparticles)
and antibiotics (vancomycin and daptomycin) in the same experi-
mental conditions. Recently, an effective method for capture and
removal bacteria was proposed by combining hydrogel with
molybdenum disulfide (MoS2) nanomaterials.[137] It used hydro-
gel with favorable biocompatibility to effectively capture and con-
fine the bacteria within the scope of ROS damage through
electrostatic interaction, while the MoS2 produced OH relying on
their intrinsic peroxidase-like activity. Treating with MoS2-
hydrogel had a decidedly antibacterial effect, decreasing inflamma-
tion and promoting wound healing.
Due to the excellent ability of ROS production, nanozymes have
drawn a lot of attention in virus inactivation. Besides peroxidase-
and catalase-like activities, iron oxide nanoparticles performed
lipoxidase activity that could induce membrane lipid peroxidation
in synthesized liposome. [138,139] If lipid peroxidation occurred in
virus envelopes, the integrity of neighboring proteins was
destroyed, causing virus inactivation. Therefore, an antiviral strat-
egy was developed by using iron oxide nanoparticles to target the
lipid envelope of the influenza virus.[140] These iron oxide
nanoparticles showed broad-spectrum antiviral activity in 12 viral
subtypes (H1 ~ H12), and their application in facemask improved
the antiviral ability against H1N1, H5N1, and H7N9 subtype. In
addition to various enzyme-like activities of nanozymes, the exten-
sive specific surface area of nanomaterials is conducive to viral
adsorption. For example, although TiO2 could generate a large
amount of HO, the adsorption of microbial phage MS2 (a common
patrol virus) on the unmodified TiO2 was little, showing a limited
antibacterial effect. However, when photocatalyst SiO2 was modi-
fied on TiO2 surface, the adsorption against MS2 was enhanced sig-
nificantly, which was 37 times than that of unmodified TiO2.[141]
5. Conclusions and prospects
Since the discovery of Fe3O4 nanozyme in 2007, nanozymes
have attracted much attention due to the same activity and similar
function as natural enzymes. Compared with natural enzymes,
nanozymes offer distinct advantages, including low cost, high sta-
bility, good durability, controllable activity, easy storage, and
excellent reusability. Therefore, they have been widely applied in
many fields, including online monitoring, imaging, anti-
immunity, cell protection, disease prevention and therapy, antibac-
terial and promote wound healing, and simulating complex biolog-
ical structure /system. With the technology development and in-
depth research, nanozymes have made great progress in theory
and application. In this review, we revealed the activity origin of
nanozymes, summarized the catalytic mechanism of common
activities, and reviewed RONS regulation-based biological applica-
tions of nanozymes. Although fruitful progress has been made,
nanozymes are still facing many challenges.
1) The activity origin of nanozymes. By structure comparison of
natural enzymes and nanozymes, it is found that they have
many similarities. However, the structure of natural
enzymes is much more complex than that of nanozymes.
Therefore, in order to obtain the same function as natural
enzymes, it is necessary to further study the microstructure
of natural enzymes and nanozymes. In addition, the activity
13
Coordination Chemistry Reviews 448 (2021) 214170
origin of nanozymes can be revealed from the perspectives
of nano effects. Perhaps it is the reason why nanozymes pos-
sess properties differed from natural enzymes. However,
related research is still very limited, thus more exploration
is needed to reveal the source of nanozyme activity in the
future.
2) Further studying the relationship between nanozyme activ-
ity and nanomaterial characteristics. Scientists have found
that nanozyme activity is closely related to the composition,
size, morphology and crystal surface of nanomaterial. For
example, the activity of metal nanozymes is associated with
the metal material: Au(1 1 1) < Ag(1 1 1) < Pt(1 1 1) < Pd(1 1 1).
[43] The peroxidase-like activity of iron oxide nanozymes is
as follows: 30 nm > 150 nm > 300 nm.[2] The glutathione
peroxidase activity of V2O5 depends on its morphology and
crystal plane.[16] However, the relevant reports are very
limited. In addition, the reason why the catalytic activity
of nanozymes is closely related to nanomaterial characteris-
tics remains to be studied and analyzed in the future.
3) Systematically researching the catalytic mechanism of dif-
ferent nanozymes. Although more and more nanozymes
and enzymatic activities have been proposed, their catalytic
mechanisms are different as nanomaterials and reaction
conditions. So far, the understanding of catalytic mechanism
is far from enough. In order to accurately control the cat-
alytic process of nanozymes, it is important to systemati-
cally research the catalytic mechanism of various
nanozymes.
4) Improve their catalytic activity and substrate selectivity. At
present, by simulating the structure of enzymes, single atom
nanozymes have shown comparable catalytic activity and
substrate selectivity [142], but most nanozymes still require
to be improved. Therefore, more efforts need to endow
nanozymes with amino acid-like structures, precisely con-
trol the coordination structure of active center atoms, and
improve atom utilization.
5) Further exploring new enzyme-mimicking activities of
nanozymes. The activity types discovered in nanozymes
are very limited, mainly including oxidoreductase and
hydrolase. Therefore, it is crucial to further explore potential
enzymatic activity of nanozymes.
6) Evaluating the biological safety of nanozymes. A remarkable
feature of nanozymes is that they can act as nanodrugs
in vivo and their catalytic behaviors can be controlled remo-
tely. However, the biological safety should be considered
first when acting in vivo. The safety and potential toxicity
are main challenges in further application of nanozymes.
Therefore, the control and decrease of potential toxicity or
developing safe and non-toxic nanozymes is worthy of our
attention.
7) Further refining the definition of related enzymes. With the
development of science and technology, scientists have
found more and more types of ‘‘enzymes”, covering natural
enzymes, artificial enzymes and nanozymes, but some are
still controversial [143]. Thus, in order to promote people’s
understanding of enzymes, it is necessary for scientists to
update or further clarify the definition and characteristics
of related enzymes.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
W. Yang, X. Yang, L. Zhu et al. Coordination Chemistry Reviews 448 (2021) 214170

Acknowledgments [44] J. Mu, L. Zhang, M. Zhao, Y. Wang, Journal of Molecular Catalysis a-Chemical
378 (2013) 30–37.
[45] I. Celardo, J.Z. Pedersen, E. Traversa, L. Ghibelli, Nanoscale 3 (2011) 1411–
This work was supported by the National Natural Science Foun- 1420.
dation of China (No. 31671922 and No. 31871875); the National [46] X. Shen, W. Liu, X. Gao, Z. Lu, X. Wu, X. Gao, J. Am. Chem. Soc. 137 (2015)
15882–15891.
Key Research and Development Program (No. 2018YFC1603704);
[47] S.S. Ali, J.I. Hardt, K.L. Quick, J.S. Kim-Han, B.F. Erlanger, T.T. Huang, C.J.
and 2115 Talent Development Program of China Agricultural Epstein, L.L. Dugan, Free Radical Biol. Med. 37 (2004) 1191–1202.
University (No. 00109016). [48] E.L.G. Samuel, D.C. Marcano, V. Berka, B.R. Bitner, G. Wu, A. Potter, R.H. Fabian,
R.G. Pautler, T.A. Kent, A.-L. Tsai, J.M. Tour, PNAS 112 (2015) 2343–2348.
[49] Y. Liu, K. Ai, X. Ji, D. Askhatova, R. Du, L. Lu, J. Shi, J. Am. Chem. Soc. 139 (2017)
856–862.
References [50] A.A. Vernekar, D. Sinha, S. Srivastava, P.U. Paramasivam, P. D’Silva, G. Mugesh,
Nat. Commun. 5 (2014).
[51] H. Ye, K. Yang, J. Tao, Y. Liu, Q. Zhang, S. Habibi, Z. Nie, X. Xia, ACS Nano 11
[1] H. Wang, K. Wan, X. Shi, Adv. Mater. 31 (2019).
(2017) 2052–2059.
[2] L. Gao, J. Zhuang, L. Nie, J. Zhang, Y. Zhang, N. Gu, T. Wang, J. Feng, D. Yang, S.
[52] H. Sun, A. Zhao, N. Gao, K. Li, J. Ren, X. Qu, Angewandte Chemie-International
Perrett, X. Yan, Nat. Nanotechnol. 2 (2007) 577–583.
Edition 54 (2015) 7176–7180.
[3] H. Wei, E. Wang, Chem. Soc. Rev. 42 (2013) 6060–6093.
[53] Z. Zhang, X. Zhang, B. Liu, J. Liu, J. Am. Chem. Soc. 139 (2017) 5412–5419.
[4] S. Wu, J. Zhang, P. Wu, Anal. Methods 11 (2019) 5081–5088.
[54] H. Tan, Y. Zhao, X. Xu, Y. Sun, Y. Li, J. Du, Microchim. Acta 187 (2020).
[5] L. Gao, X. Gao, X. Yan, Kinetics and Mechanisms for Nanozymes, Springer,
[55] F. Li, N. Li, C. Xue, H. Wang, Q. Chang, H. Liu, J. Yang, S. Hu, Chem. Eng. J. 382
Singapore, 2020.
(2020).
[6] H. She, B. Wang, Finite Elem. Anal. Des. 45 (2009) 463–467.
[56] T. Cai, G. Fang, X. Tian, J.-J. Yin, C. Chen, C. Ge, ACS Nano 13 (2019) 12694–
[7] H. Dong, Y. Fan, W. Zhang, N. Gu, Y. Zhang, Bioconjug. Chem. 30 (2019) 1273–
12702.
1296.
[57] Y. Ding, G. Wang, F. Sun, Y. Lin, ACS Appl. Mater. Interfaces 10 (2018) 32567–
[8] Y. Sun, C. Zhao, N. Gao, J. Ren, X. Qu, Chemistry-a European Journal 23 (2017)
32578.
18146–18150.
[58] D. Yang, Q. Li, S.K. Tammina, Z. Gao, Y. Yang, Sensors and Actuators B-
[9] M. Sun, L. Xu, A. Qu, P. Zhao, T. Hao, W. Ma, C. Hao, X. Wen, F.M. Colombari, A.
Chemical 319 (2020).
F. de Moura, N.A. Kotov, C. Xu, H. Kuang, Nat. Chem. 10 (2018) 821–830.
[59] X. Wu, T. Chen, Y. Chen, G. Yang, J. Mater. Chem. B 8 (2020) 2650–2659.
[10] F. Li, S. Li, X. Guo, Y. Dong, C. Yao, Y. Liu, Y. Song, X. Tan, L. Gao, D. Yang,
[60] S. Lin, Y. Cheng, H. Zhang, X. Wang, Y. Zhang, Y. Zhang, L. Miao, X. Zhao, H.
Angewandte Chemie-International Edition 59 (2020) 11087–11092.
Wei, Small 16 (2020).
[11] N.C. Veitch, Phytochemistry 65 (2004) 249–259.
[61] B. Xu, Y. Cui, W. Wang, S. Li, C. Lyu, S. Wang, W. Bao, H. Wang, M. Qin, Z. Liu,
[12] C. Zhao, C. Xiong, X. Liu, M. Qiao, Z. Li, T. Yuan, J. Wang, Y. Qu, X. Wang, F.
W. Wei, H. Liu, Adv. Mater. 32 (2020).
Zhou, Q. Xu, S. Wang, M. Chen, W. Wang, Y. Li, T. Yao, Y. Wu, Y. Li, Chem.
[62] M. Wang, M. Chang, Q. Chen, D. Wang, C. Li, Z. Hou, J. Lin, D. Jin, B. Xing,
Commun. 55 (2019) 2285–2288.
Biomaterials 252 (2020).
[13] W. Du, Research on theory and engineering application of nano material
[63] T. Pirmohamed, J.M. Dowding, S. Singh, B. Wasserman, E. Heckert, A.S.
chemistry, University of Electronic Science and Technology Press, Chengdu,
Karakoti, J.E.S. King, S. Seal, W.T. Self, Chem. Commun. 46 (2010) 2736–2738.
2018.
[64] D.A. Giannakoudakis, Y. Hu, M. Florent, T.J. Bandosz, Nanoscale Horiz. 2
[14] L. Cao, J. Huang, X. Zhao, J. Li, Y. Zhuo, F. Yu, S. Zhou, X. Zhang, W. Zhou, Y. Li,
(2017) 356–364.
X. He, Wet chemical synthesis and photocatalytic properties of tungstate
[65] C. Hao, R. Gao, Y. Li, L. Xu, M. Sun, C. Xu, H. Kuang, Angewandte Chemie-
nanomaterials, 2017.
International Edition 58 (2019) 7371–7374.
[15] S. Deshpande, S. Patil, S. Kuchibhatla, S. Seal, Appl. Phys. Lett. 87 (2005).
[66] J.C. Conesa, Surf. Sci. 339 (1995) 337–352.
[16] S. Ghosh, P. Roy, N. Karmodak, E.D. Jemmis, G. Mugesh, Angewandte Chemie-
[67] V. Baldim, F. Bedioui, N. Mignet, I. Margaill, J.F. Berret, Nanoscale 10 (2018)
International Edition 57 (2018) 4510–4515.
6971–6980.
[17] Y. Yang, Z. Mao, W. Huang, L. Liu, J. Li, J. Li, Q. Wu, Sci. Rep. 6 (2016).
[68] E.G. Heckert, A.S. Karakoti, S. Seal, W.T. Self, Biomaterials 29 (2008) 2705–
[18] T. Naganuma, Nano Res. 10 (2017) 199–217.
2709.
[19] M. Peng, C. Dong, R. Gao, D. Xiao, H. Liu, D. Ma, ACS Central Science (2020).
[69] C.A. Ferreira, D. Ni, Z.T. Rosenkrans, W. Cai, Nano Res. 11 (2018) 4955–4984.
[20] J. Wu, X. Wang, Q. Wang, Z. Lou, S. Li, Y. Zhu, L. Qin, H. Wei, Chem. Soc. Rev. 48
[70] M. Lu, C. Wang, Y. Ding, M. Peng, W. Zhang, K. Li, W. Wei, Y. Lin, Chem.
(2019) 1004–1076.
Commun. 55 (2019) 14534–14537.
[21] B. Rogers, S. Pennathur, J. Adams, Nanotechnology : understanding small
[71] N. Singh, M.A. Savanur, S. Srivastava, P. D’Silva, G. Mugesh, Angewandte
systems /, 2nd ed., CRC Press, 2011.
Chemie-International Edition 56 (2017) 14267–14271.
[22] Y. Huang, J. Ren, X. Qu, Chem. Rev. 119 (2019) 4357–4412.
[72] C. Hao, A. Qu, L. Xu, M. Sun, H. Zhang, C. Xu, H. Kuang, J. Am. Chem. Soc. 141
[23] X. Ai, Y. Wang, X. Hou, L. Yang, C. Zheng, L. Wu, Analyst 138 (2013) 3494–
(2019) 1091–1099.
3501.
[73] H. Xiang, W. Feng, Y. Chen, Adv. Mater. 32 (2020).
[24] Z. Chen, J.-J. Yin, Y.-T. Zhou, Y. Zhang, L. Song, M. Song, S. Hu, N. Gu, ACS Nano
[74] B. Yang, Y. Chen, J. Shi, Chem. Rev. 119 (2019) 4881–4985.
6 (2012) 4001–4012.
[75] R. Singh, S. Singh, Colloids and Surfaces B-Biointerfaces 175 (2019) 625–635.
[25] R.C.C. Costa, M.F.F. Lelis, L.C.A. Oliveira, J.D. Fabris, J.D. Ardisson, R. Rios, C.N.
[76] S. Das, C.J. Neal, J. Ortiz, S. Seal, Nanoscale 10 (2018) 21069–21075.
Silva, R.M. Lago, J. Hazard. Mater. 129 (2006) 171–178.
[77] F. Dashtestani, H. Ghourchian, A. Najafi, Bioorg. Chem. 80 (2018) 621–630.
[26] H. Niu, D. Zhang, S. Zhang, X. Zhang, Z. Meng, Y. Cai, J. Hazard. Mater. 190
[78] J. Gao, S. Wang, Z. Wang, Biomaterials 135 (2017) 62–73.
(2011) 559–565.
[79] S. Munir, A.A. Shah, H. Rahman, M. Bilal, M.S.R. Rajoka, A.A. Khan, M.
[27] J.F. Perez-Benito, J. Phys. Chem. A 108 (2004) 4853–4858.
Khurshid, Biotechnol. Lett. 42 (2020) 357–373.
[28] H. Yang, R. Yang, P. Zhang, Y. Qin, T. Chen, F. Ye, Microchim. Acta 184 (2017)
[80] W. Zhen, Y. Liu, L. Lin, J. Bai, X. Jia, H. Tian, X. Jiang, Angewandte Chemie-
4629–4635.
International Edition 57 (2018) 10309–10313.
[29] D. Jiang, D. Ni, Z.T. Rosenkrans, P. Huang, X. Yan, W. Cai, Chem. Soc. Rev. 48
[81] X. Li, M. Qi, X. Sun, M.D. Weir, F.R. Tay, T.W. Oates, B. Dong, Y. Zhou, L. Wang,
(2019) 3683–3704.
H.H.K. Xu, Acta Biomater. 94 (2019) 627–643.
[30] R. Zhao, X. Zhao, X. Gao, Chemistry-a European Journal 21 (2015) 960-+.
[82] S. Zhao, Y. Li, Q. Liu, S. Li, Y. Cheng, C. Cheng, Z. Sun, Y. Du, C.J. Butch, H. Wei,
[31] Y. Song, K. Qu, C. Zhao, J. Ren, X. Qu, Adv. Mater. 22 (2010) 2206–2210.
Adv. Funct. Mater. 30 (2020).
[32] J. Dong, L. Song, J.-J. Yin, W. He, Y. Wu, N. Gu, Y. Zhang, ACS Appl. Mater.
[83] J. Yao, Y. Cheng, M. Zhou, S. Zhao, S. Lin, X. Wang, J. Wu, S. Li, H. Wei, Chem.
Interfaces 6 (2014) 1959–1970.
Sci. 9 (2018) 2927–2933.
[33] J. Mu, Y. Wang, M. Zhao, L. Zhang, Chem. Commun. 48 (2012) 2540–2542.
[84] Z. Miao, S. Jiang, M. Ding, S. Sun, Y. Ma, M.R. Younis, G. He, J. Wang, J. Lin, Z.
[34] W. Zhang, S. Hu, J.-J. Yin, W. He, W. Lu, M. Ma, N. Gu, Y. Zhang, J. Am. Chem.
Cao, P. Huang, Z. Zha, Nano Lett. 20 (2020) 3079–3089.
Soc. 138 (2016) 5860–5865.
[85] D. Yu, M. Ma, Z. Liu, Z. Pi, X. Du, J. Ren, X. Qu, Biomaterials 255 (2020).
[35] S. Grundner, M.A.C. Markovits, G. Li, M. Tromp, E.A. Pidko, E.J.M. Hensen, A.
[86] A. Sood, M.S. Granick, N.L. Tomaselli, Advances in wound care 3 (2014) 511–529.
Jentys, M. Sanchez-Sanchez, J.A. Lercher, Nat. Commun. 6 (2015).
[87] Y. Guan, M. Li, K. Dong, N. Gao, J. Ren, Y. Zheng, X. Qu, Biomaterials 98 (2016)
[36] Q. Wang, H. Wei, Z. Zhang, E. Wang, S. Dong, Trac-Trends in Analytical
92–102.
Chemistry 105 (2018) 218–224.
[88] N. Gao, K. Dong, A. Zhao, H. Sun, Y. Wang, J. Ren, X. Qu, Nano Res. 9 (2016)
[37] L. Wang, S. Li, X. Zhang, Y. Huang, Talanta 216 (2020).
1079–1090.
[38] X. Zhang, A. Yuan, X. Mao, Q. Chen, Y. Huang, Sensors and Actuators B-
[89] C. Ren, D. Li, Q. Zhou, X. Hu, Biomaterials 232 (2020).
Chemical 299 (2019).
[90] K. Zhang, M. Tu, W. Gao, X. Cai, F. Song, Z. Chen, Q. Zhang, J. Wang, C. Jin, J. Shi,
[39] Z. Jin, G. Xu, Y. Niu, X. Ding, Y. Han, W. Kong, Y. Fang, H. Niu, Y. Xu, J. Mater.
X. Yang, Y. Zhu, W. Gu, B. Hu, Y. Zheng, H. Zhang, M. Tian, Nano Lett. 19 (2019)
Chem. B 8 (2020) 3513–3518.
2812–2823.
[40] X.J. Yang, R.S. Li, C.M. Li, Y.F. Li, C.Z. Huang, Talanta 215 (2020).
[91] X. Mu, H. He, J. Wang, W. Long, Q. Li, H. Liu, Y. Gao, L. Ouyang, Q. Ren, S. Sun, J.
[41] M. Comotti, C. Della Pina, E. Falletta, M. Rossi, Adv. Synth. Catal. 348 (2006)
Wang, J. Yang, Q. Liu, Y. Sun, C. Liu, X.-D. Zhang, W. Hu, Nano Lett. 19 (2019)
313–316.
4527–4534.
[42] R. Ragg, F. Natalio, M.N. Tahir, H. Janssen, A. Kashyap, D. Strand, S. Strand, W.
[92] X. Mu, J. Wang, Y. Li, F. Xu, W. Long, L. Ouyang, H. Liu, Y. Jing, J. Wang, H. Dai,
Tremel, ACS Nano 8 (2014) 5182–5189.
Q. Liu, Y. Sun, C. Liu, X.-D. Zhang, ACS Nano 13 (2019) 1870–1884.
[43] J. Li, W. Liu, X. Wu, X. Gao, Biomaterials 48 (2015) 37–44.

14
W. Yang, X. Yang, L. Zhu et al.
[93] S. Gao, H. Lin, H. Zhang, H. Yao, Y. Chen, J. Shi, Adv. Sci. 6 (2019).
[94] H. Lin, Y. Chen, J. Shi, Chem. Soc. Rev. 47 (2018) 1938–1958.
[95] G. Yang, L. Xu, Y. Chao, J. Xu, X. Sun, Y. Wu, R. Peng, Z. Liu, Nat. Commun. 8
(2017).
[96] D. Wang, H. Wu, S.Z.F. Phua, G. Yang, W.Q. Lim, L. Gu, C. Qian, H. Wang, Z. Guo,
H. Chen, Y. Zhao, Nat. Commun. 11 (2020).
[97] L. Fan, X. Xu, C. Zhu, J. Han, L. Gao, J. Xi, R. Guo, ACS Appl. Mater. Interfaces 10
(2018) 4502–4511.
[98] S. Liang, X. Deng, G. Xu, X. Xiao, M. Wang, X. Guo, P.A. Ma, Z. Cheng, D. Zhang,
J. Lin, Adv. Funct. Mater. 30 (2020).
[99] L. Li, Z. Yang, W. Fan, L. He, C. Cui, J. Zou, W. Tang, O. Jacobson, Z. Wang, G. Niu,
S. Hu, X. Chen, Adv. Funct. Mater. 30 (2020).
[100] C. Fang, Z. Deng, G. Cao, Q. Chu, Y. Wu, X. Li, X. Peng, G. Han, Adv. Funct.
Mater. 30 (2020).
[101] Z. Wang, Y. Zhang, E. Ju, Z. Liu, F. Cao, Z. Chen, J. Ren, X. Qu, Nat. Commun. 9
(2018).
[102] A. Zhang, Q. Zhang, G. Alfranca, S. Pan, Z. Huang, J. Cheng, Q. Ma, J. Song, Y.
Pan, J. Ni, L. Ma, D. Cui, Nano Res. 13 (2020) 160–172.
[103] D.-W. Zheng, Q. Lei, J.-Y. Zhu, J.-X. Fan, C.-X. Li, C. Li, Z. Xu, S.-X. Cheng, X.-Z.
Zhang, Nano Lett. 17 (2017) 284–291.
[104] P.A. Ma, H. Xiao, C. Yu, J. Liu, Z. Cheng, H. Song, X. Zhang, C. Li, J. Wang, Z. Gu, J.
Lin, Nano Lett. 17 (2017) 928–937.
[105] Y. Chen, H. Zhong, J. Wang, X. Wan, Y. Li, W. Pan, N. Li, B. Tang, Chem. Sci. 10
(2019) 5773–5778.
[106] L. Feng, Z. Dong, C. Liang, M. Chen, D. Tao, L. Cheng, K. Yang, Z. Liu,
Biomaterials 181 (2018) 81–91.
[107] Y. Li, K.-H. Yun, H. Lee, S.-H. Goh, Y.-G. Suh, Y. Choi, Biomaterials 197 (2019)
12–19.
[108] P. Hu, T. Wu, W. Fan, L. Chen, Y. Liu, D. Ni, W. Bu, J. Shi, Biomaterials 141
(2017) 86–95.
[109] Y.-C. Ma, Y.-H. Zhu, X.-F. Tang, L.-F. Hang, W. Jiang, M. Li, M.I. Khan, Y.-Z. You,
Y.-C. Wang, Biomater. Sci. 7 (2019) 2740–2748.
[110] Y. Zhang, F. Wang, C. Liu, Z. Wang, L. Kang, Y. Huang, K. Dong, J. Ren, X. Qu,
ACS Nano 12 (2018) 651–661.
[111] F. Gao, J. Wu, H. Gao, X. Hu, L. Liu, A.C. Midgley, Q. Liu, Z. Sun, Y. Liu, D. Ding, Y.
Wang, D. Kong, X. Huang, Biomaterials 230 (2020).
[112] H. Wu, L. Liu, L. Song, M. Ma, N. Gu, Y. Zhang, ACS Nano 13 (2019) 14013–
14023.
[113] S.K. Maji, A.K. Mandal, N. Kim Truc, P. Borah, Y. Zhao, ACS Appl. Mater.
Interfaces 7 (2015) 9807–9816.
[114] K. Fan, J. Xi, L. Fan, P. Wang, C. Zhu, Y. Tang, X. Xu, M. Liang, B. Jiang, X. Yan, L.
Gao, Nat. Commun. 9 (2018).
[115] M. Huo, L. Wang, Y. Chen, J. Shi, Nat. Commun. 8 (2017).
[116] Z. Wang, G. Li, Y. Gao, Y. Yu, P. Yang, B. Li, X. Wang, J. Liu, K. Chen, J. Liu, W.
Wang, Chem. Eng. J. 404 (2020) 125574.
[117] Z. Ma, L. Wu, K. Han, H. Han, Nanoscale Horiz. 4 (2019) 1124–1131.
[118] S. Dong, Y. Dong, T. Jia, S. Liu, J. Liu, D. Yang, F. He, S. Gai, P. Yang, J. Lin, Adv.
Mater. 32 (2020).
15
Coordination Chemistry Reviews 448 (2021) 214170
[119] S.K. Maji, S. Yu, K. Chung, M.S. Ramasamy, J.W. Lim, J. Wang, H. Lee, D.H. Kim,
ACS Appl. Mater. Interfaces 10 (2018) 42068–42076.
[120] Y. Hao, Y. Liu, Y. Wu, N. Tao, D. Lou, J. Li, X. Sun, Y.-N. Liu, Biomater. Sci. 8
(2020) 1830–1839.
[121] S. Li, L. Shang, B. Xu, S. Wang, K. Gu, Q. Wu, Y. Sun, Q. Zhang, H. Yang, F. Zhang,
L. Gu, T. Zhang, H. Liu, Angewandte Chemie-International Edition 58 (2019)
12624–12631.
[122] X. Zhong, X. Wang, L. Cheng, Y.A. Tang, G. Zhan, F. Gong, R. Zhang, J. Hu, Z. Liu,
X. Yang, Adv. Funct. Mater. 30 (2020).
[123] Y. Chen, Z.-H. Li, J.-J. Hu, S.-Y. Peng, L. Rong, Y. Sun, X.-Z. Zhang, Nanoscale
Horiz. 5 (2020) 283–293.
[124] F. Liu, L. Lin, Y. Zhang, Y. Wang, S. Sheng, C. Xu, H. Tian, X. Chen, Adv. Mater.
31 (2019).
[125] X. Yang, Y. Yang, F. Gao, J.-J. Wei, C.-G. Qian, M.-J. Sun, Nano Lett. 19 (2019)
4334–4342.
[126] S. Liang, X. Deng, Y. Chang, C. Sun, S. Shao, Z. Xie, X. Xiao, P.A. Ma, H. Zhang, Z.
Cheng, J. Lin, Nano Lett. 19 (2019) 4134–4145.
[127] C. Liu, L. Luo, L. Zeng, J. Xing, Y. Xia, S. Sun, L. Zhang, Z. Yu, J. Yao, Z. Yu, O.U.
Akakuru, M. Saeed, A. Wu, Small 14 (2018).
[128] L. Feng, B. Liu, R. Xie, D. Wang, C. Qian, W. Zhou, J. Liu, D. Jana, P. Yang, Y.
Zhao, Adv. Funct. Mater. (2020).
[129] W. Zhen, Y. Liu, W. Wang, M. Zhang, W. Hu, X. Jia, C. Wang, X. Jiang,
Angewandte Chemie-International Edition 59 (2020) 9491–9497.
[130] C. Wei, Y. Liu, X. Zhu, X. Chen, Y. Zhou, G. Yuan, Y. Gong, J. Liu, Biomaterials
238 (2020).
[131] J. Wang, L. Fang, P. Li, L. Ma, W. Na, C. Cheng, Y. Gu, D. Deng, Nano-Micro
Letters 11 (2019).
[132] Y. Zhang, P. Sun, L. Zhang, Z. Wang, F. Wang, K. Dong, Z. Liu, J. Ren, X. Qu, Adv.
Funct. Mater. 29 (2019).
[133] Z. Wang, K. Dong, Z. Liu, Y. Zhang, Z. Chen, H. Sun, J. Ren, X. Qu, Biomaterials
113 (2017) 145–157.
[134] Z. Liu, F. Wang, J. Ren, X. Qu, Biomaterials 208 (2019) 21–31.
[135] J. Xi, G. Wei, L. An, Z. Xu, Z. Xu, L. Fan, L. Gao, Nano Lett. 19 (2019) 7645–7654.
[136] J. Shan, X. Li, K. Yang, W. Xiu, Q. Wen, Y. Zhang, L. Yuwen, L. Weng, Z. Teng, L.
Wang, ACS Nano 13 (2019) 13797–13808.
[137] Y. Sang, W. Li, H. Liu, L. Zhang, H. Wang, Z. Liu, J. Ren, X. Qu, Adv. Funct. Mater.
29 (2019).
[138] L. Wang, Y. Min, D. Xu, F. Yu, W. Zhou, A. Cuschieri, Chem. Commun. 50
(2014) 11147–11150.
[139] F. Xiong, H. Wang, Y. Feng, Y. Li, X. Hua, X. Pang, S. Zhang, L. Song, Y. Zhang, N.
Gu, Sci. Rep. 5 (2015).
[140] T. Qin, R. Ma, Y. Yin, X. Miao, S. Chen, K. Fan, J. Xi, Q. Liu, Y. Gu, Y. Yin, J. Hu, X.
Liu, D. Peng, L. Gao, Theranostics 9 (2019) 6920–6935.
[141] M.V. Liga, S.J. Maguire-Boyle, H.R. Jafry, A.R. Barron, Q. Li, Environ. Sci.
Technol. 47 (2013) 6463–6470.
[142] J. Xi, R. Zhang, L. Wang, W. Xu, Q. Liang, J. Li, J. Jiang, Y. Yang, X. Yan, K. Fan, L.
Gao, Adv. Funct. Mater. 31 (2021).
[143] S. Scott, H. Zhao, A. Dey, T.B. Gunnoe, ACS Catal. 10 (2020) 14315–14317.