PROGRESS REPORT

Nanoenzymes [Link]

Recent Advances in Nanozyme Research

Hui Wang, Kaiwei Wan, and Xinghua Shi*

inflammatory response to combat infec-

As a new generation of artificial enzymes, nanozymes have the advantages tions and can also react with many
of high catalytic activity, good stability, low cost, and other unique proper- important biomolecules including pro-
ties of nanomaterials. Due to their wide range of potential applications, teins, lipids, and nucleic acid polymers
(RNA and DNA).[7] Low dosage of ROS
they have become an emerging field bridging nanotechnology and biology,
plays important roles in signal transduc-
attracting researchers in various fields to design and synthesize highly tion, cell proliferation/migration/differen-
catalytically active nanozymes. However, the thorough understanding of tiation, and body defense against pathogen
experimental phenomena and the mechanisms beneath practical applica- invasion. However, abnormally elevated
tions of nanozymes limits their rapid development. Herein, the progress ROS level can destroy redox homeostasis
of experimental and computational research of nanozymes on two issues and cause oxidative stress and serious
damage of structure and function of mac-
over the past decade is briefly reviewed: (1) experimental development of
romolecules in the cell. Research during
new nanozymes mimicking different types of enzymes. This covers their the last decade has shown that oxidative
structures and applications ranging from biosensing and bioimaging to thera- stress could lead to diseases such as chronic
peutics and environmental protection. (2) The catalytic mechanism proposed inflammation and eventually diabetes,
by experimental and theoretical study. The challenges and future directions of cancer, as well as cardiovascular, neuro-
logical, and pulmonary diseases.[8] Enzyme
computational research in this field are also discussed.
systems (e.g., superoxide dismutase (SOD),
glutathione peroxidase (GPx), and catalase)
are responsible for protecting cells from
1. Introduction the detrimental effects of ROS by modulating the intracellular
ROS level.
Nanomaterials typically refer to materials with size (at least Nanozyme can also modulate the ROS level in cells
in one dimension) of 1–100 nm. At this scale, materials may (Figure 2).[9] The ROS scavenging abilities of nanozymes largely
possess unique chemical, physical, biological, and mechanical originate from the SOD mimicking activities, which convert
properties that are distinct from bulk ones. Nanozymes refer superoxide into H2O2 and subsequently to O2 and H2O, and
to nanomaterials with enzyme mimicking activities.[1] It has thus reduce the intracellular ROS level and enhance cell via-
become a hot topic in recent years due to the facile synthesis,[2] bility. The generation of ROS originates from their peroxidases
tunable catalytic activities,[3] high stability, low cost, and ease of (POD) activities, which convert H2O2 to OH· radicals, and oxi-
treatment.[4] Nanozymes are promising alternatives for natural dase activities, which convert O2 to H2O2. Outside the cell, ROS
enzymes in various applications.[1a,5] can react with biologically active molecules (such as glucose,
In enzymes-involved cellular metabolism, oxygen undergoes dopamine, glutathione, and adenosine triphosphate), organic
a series of one-electron reductions, which in turn lead to the compound (such as phenol and dyes), and pollutants from
formation of reactive oxygen species (ROS), including O2·−, aqueous solutions. Thus the nanozymes could play important
O2·2−, OH·, OOH· radicals, H2O2, and so on (Figure 1).[6] roles in in vitro test and environmental protection.[10]
ROS are involved in various signaling pathways in response Earlier reports on nanozymes mainly focused on the aspect
to the change of external conditions, which is a part of the of experimental study and rarely focused on the theoretical
work and mechanism clarification. In this progress report,
Dr. H. Wang, K. Wan, Prof. X. Shi we first introduce various nanozymes and highlight recent
CAS Key Laboratory for Nanosystem and Hierarchy Fabrication experimental development of new nanozymes that have been
CAS Center for Excellence in Nanoscience investigated to mimic various enzymes. Then we review their
National Center for Nanoscience and Technology
Chinese Academy of Sciences applications in various fields including biosensing, bioimaging,
Beijing 100190, P. R. China therapeutics, and environmental protection. At last, we sum-
E-mail: shixh@[Link] marize the catalytic mechanisms and address the challenges of
Dr. H. Wang, K. Wan, Prof. X. Shi experimental and computational research in this field.
School of Nanoscience and Technology
University of Chinese Academy of Sciences
Beijing 100049, P. R. China
The ORCID identification number(s) for the author(s) of this article 2. The Structure of Nanozymes
can be found under [Link]
Issues of material design for high catalytical activity, selectivity,
DOI: 10.1002/adma.201805368 and durability are recently accentuated. Among them

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Hui Wang obtained her Ph.D.

from Jilin University in 2013.
After postdoctoral work in
the Institute of High Energy
Physics, Chinese Academy
of Sciences for three years,
she has worked as a research
associate in the group of
Prof. Xinghua Shi since 2016.
Her research interests include
the electronic structure
simulations and characteriza-
tion of nanomaterials with QM and MM methods, and
investigation of their catalytic mechanism.
Figure 1. Generation and elimination of ROS in vivo. Reproduced with
permission.[1b] Copyright 2018, Science Press.
Xinghua Shi obtained his
nanoparticle (NP) based catalysts have attracted increasing
Ph.D. from Brown University,
interest. Up to now, various NPs made of metals, metal oxides,
USA, in 2010. He then
and carbons have been reported to resemble the functions of
worked in the Institute
various enzymes-like oxidase, peroxidase, catalase, and super-
of Mechanics, Chinese
oxide dismutase.[11] Recent studies revealed that activities of
Academy of Sciences as
NPs are greatly dependent on the particle size, shape, and
an Associate Professor
surface facets, which could be affected by charges, coatings,
and in 2016, he moved to
dopings, loadings, and external fields. Thanks to the fast devel-
the National Center for
opment of nanotechnology, the size, morphology, and facets of
Nanoscience and Technology
NPs could be precisely controlled.[12] The understanding of the
as a Professor. His research
structure–function relation is then timely urgent.
interests include multiscale
It has been found that the specific activity of nanozymes is
calculation, self-assembly of nanostructures, drug delivery,
size dependent, which can be explained as follows. First, coor-
and biomechanics.
dinated surface atoms in small-sized NPs can strongly adsorb
reactant species. Surface defects like steps, kinks, adatoms,
and vacancies are coordinatively unsaturated and therefore core@shell, doping, intermetallic compounds, shape control,
reactive. Due to the increased surface-area-to-volume ratio, and NP confinement.[12a]
the number of unsaturated sites increases as the particle size It is known that in nature, multistep cascade reactions could
decreases. On the other hand, the adsorption energy decreases be accomplished by collaborative work of several enzymes.[13] To
with the particle size because for very small NPs with only a mimic the complex functions of natural systems and overcome
few atom layers, the buffering effect of the subsurface layers the moderate activity of a single nanozyme, many hybrid cata-
will be exhausted and the electrons for substrate bonding lysts have been prepared by the attachment of catalysts to sup-
are no longer available. Around one optimal size, the activity ports through links or by cocatalyst interactions. Thanks to the
origin can be understood by the balance of the two factors. The development of nanotechnology, significant progress has been
durability of NPs also decreases with the NP size. To maintain made in the design of various functional NPs as highly active
performance without loss of activity, increasing NP stability enzyme-like catalysts.[5b,12a,f,14] For instance, the synergistic
becomes a key. There are various methods proposed to inhibit effect of enhanced enzyme-like activity was observed for g-C3N4-
atomic dissolution of NPs and their aggregation, such as AuNPs hybrid by growing AuNPs on ultrathin graphitic carbon

Figure 2. Nanozymes regulate ROS balance by their intrinsic redox reactions. Reproduced with permission.[1d] Copyright 2018, Science Press.

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nitride,[14i] Fe3O4[3c] and 3D porous grapheme,[15] AuNPs@MIL- (QDs), and graphene oxides (GO) have been used to amplify
101@GOx, and AuNPs@MIL-101@LOx integrative nanozymes the detecting signals of thrombin voltammetry.[36]
by assembling glucose oxidase (GOx) and lactate oxidase (LOx) In contrast, in vivo diagnostics are conducted within a living
onto AuNPs@MIL-101.[16] body.[33] In biomedical imaging, the in vivo sensing of cells/
Numerous synthesis strategies of nanozymes, such as encap- organs is important. With hydrogen peroxide, iron oxide NPs
sulating organic enzymes into NPs, have attracted broad atten- can catalyze the oxidation of peroxidase substrates, producing a
tion owing to the superior catalytic performance by combining color reaction similar to natural peroxidases. Through the per-
the advantages of both natural/artificial organic enzymes oxidase activity of the iron oxide core, nanozymes are capable
and NPs.[17] Among these applications, bioconjugation is a of targeting TfR1 without additional ligands, and visualizing
serious challenge. In the biological applications such as target tumor tissues.[37] Fe3O4-GOx@DMSNs nanozyme has been
drug delivery, biosensing, and bioimaging, it is necessary to used to generate harmful OH· in cancer cells imaged by ROS
graft nanozymes with affinity ligands. However, nanozymes fluorescent probe. By analyzing the corresponding fluores-
might loss catalytic activity if their surface is densely capped cence intensity, the distribution of glucose in cancer cells could
since the reaction might take place on the surface of nanozymes be mapped.[30c] The MnO-based nanosystem with selective
(e.g., oxidase-like activity).[18] Because of the complexity of sur- response toward superoxide radicals is capable of enhancing
face, so far there is no universal way to achieve bioconjugation. the magnetic resonance (MR) imaging contrast by sequential
A very popular way for nanoceria is to use polysaccharides such catalytic reaction.[38] Based on the catalase-like activity of MnO2
as dextran.[19] Another appropriate way is to load homogeneous toward H2O2, the in situ oxygen generation and upconversion
catalysts into organic particles. Driven by practical applications luminescent imaging can be achieved simultaneously, which
of nanozymes, research on this field is fast growing.[5c,20] is capable of achieving the desirable cancer theranostics via
Metal NPs templated on proteins have been synthesized with the oxygen-elevated synergetic radio/photodynamic therapy
high peroxidase-like activities. Similarly, the rich physiochem- (PDT).[39] The O2 molecules generated in the catalase-like
ical properties of DNA have also allowed researchers to develop activity of Prussian Blue (KFe3+[Fe2+(CN)6]) NPs can be used
novel nanozymes with DNA metallization. It has been shown as an ultrasound (US) contrast agent to enhance US imaging.
that DNA could be used to template the growth of Pt, Ag, and Moreover, some of the Fe3+ centers are accessible to water
bimetallic NPs to mimic the activity of peroxidase and the influ- co-ordination to form paramagnetic oxygen bubbles, which is
ence of the DNA polymorphologies on the nanozyme activity beneficial for shortening the T1 relaxation time and developing
has been studied.[21] A series of biomolecules have also been pre- NP-based T1 MR imaging contrast agents.[40]
pared to mimic the structure and function of natural enzymes.[22]

3.2. Disease Therapy

3. Applications of Nanozymes
Due to the advantages of NPs for medical applications, a broad
Various nanozyme based applications have been extensively range of functional NPs have been explored for diagnosing
explored, including in vitro[23] and in vivo[24] biosensors, and and treating various diseases, such as cancer and Alzheimer’s
antibacterial[25] and disease therapies, such as cancer theranos- disease, many of which are due to ROS level abnormalities.[41]
tics,[26] bone marrow therapy,[27] and wound healing.[28] In addi- Nanozymes can modulate the ROS level in cells, thus have
tion, environmental protection[29] is also an important area. In been explored for potential therapeutics through eliminating
the following we briefly introduce the advance of nanozymes ROS. Take leukemia therapy as an example, the intracellular
in these fields (Figure 3[14d,23,24,30]). For clarification, we also oxidation–reduction homeostasis increases the level of ROS in
summarize these advances in Table 1.[12b,e,f,14b,c,e–g,i,j,16,28,31] acute myeloid leukemia cells, not only causing DNA damage,
increasing gene instability, but also raising the expression of
resistance-related proteins, prompting cells to return to the
3.1. Biosensors bone marrow, and forming tiny residual lesions. Excellent ROS
scavenging abilities of nanozymes such as V2O5-PDA-MnO2 can
In vitro diagnostics (IVD) tests are performed in tubes from successfully build an anti-inflammation model.[14c] Nanozymes,
biological samples of living body (e.g., blood and urine) to e.g., GOx-Fe3O4@DMSNs, can also generate highly toxic ROS
determine the presence of disease.[32] Due to the development to kill cancer cells based on the specific microenvironment.[30c]
of nanotechnology, the design of NP-based IVD tools has made At the same time, the cancer cells would be starved by the con-
great progress.[33] Peroxidase-like NPs have been developed for sumption of glucose. The redox concentration of H2O2 and O2
enzyme reactions to detect active molecules such as glucose, can promote or slow the progression of the wound healing pro-
dopamine, xanthine, glutathione, adenosine triphosphate, cess. The NPs may play roles on bone therapy by improving
metal ions, and enzyme inhibitors.[14f,16,31w,34] The use of these bone regeneration or treating bone disorders.[42]
nanozymes as colorimetric reporters yields high specificity and The electronic structure and catalectic activity of nanozyme
efficiency. For instance, the V2O5-PDA-Au nanozyme could are sensitive to external factors, such as photo and US, elec-
detect glucose with high sensitivity and selectivity.[14c] By using tric, and magnetic fields. The applications in cancer therapy
Pt@CuMOFs-hemin/G-quadruplex-GOx nanozyme, an elec- with these strategies include chemodynamic therapy (CDT),
trochemical impedimetric aptasensor was proposed for carci- PDT and sonodynamic therapy (SDT). CDT is an emerging
noembryonic antigen.[35] NPs including Au, Pt, quantum dots treatment that uses endogenous chemical energy to produce

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Figure 3. Illustration of the application of nanozymes in different fields: a) Biosensor in vivo and in vitro. 1. In vitro: Reproduced with permission.[23]
Copyright 2008, American Chemical Society. 2. In vivo: Reproduced with permission.[24] Copyright 2016, American Chemical Society. b) Detection
of tumor cells. Reproduced with permission.[30a] Copyright 2017, The Royal Society of Chemistry. c) Improvement of cellular antioxidant capacity.
Reproduced with permission.[30b] Copyright 2010, American Chemical Society. d) Tumor suppression. Reproduced with permission under the terms
of the CC-BY 4.0 license.[30c] Copyright 2017, The Authors. Published by Nature Publishing Group. e) Acceleration of wound healing. Reproduced with
permission.[30d] Copyright 2016, Wiley-VCH. f) Inhibition of biofilm formation. Reproduced with permission.[14d] Copyright 2016, Wiley-VCH.

ROS and induce cell death without external energy input.[43] Thus, nanozymes can promote the efficiency of the antioxida-
Other therapies usually consist of three components: a photo/ tive effect by active H2O2.
radiation/sonosensitizer, light/US, and tissue oxygen. The gen- Metallic NPs such as Cu, Au, Pt, Ag, and Pd could play a
eration of ROS causes cancer cells to perish directly or indirectly. role in this field and have shown promising results. Transmis-
Some nanozymes can trigger the decomposition of endogenous sion electron microscopy (TEM) analysis confirmed that small
H2O2 in the tumor microenvironment as catalase to generate O2 PtNPs (1–3 nm) enter bacteria directly and show significant
to attenuate hypoxia and enhance radiation response, thus the bacteriotoxic properties.[45] The lower zeta potential of PtNPs
therapeutic efficacy of PDT and SDT can be enhanced by the could induce the rupture of membrane and cell walls, subse-
integration of photosensitizer with nanozyme to regulate the quently the release of cytoplasmic content.[46] Pectin-capped
tumor microenvironment for combinational therapy. PtNPs (2–5 nm) were found to be toxic against Gram positive
and Gram negative bacteria in vitro and in vivo.[45,46]

3.3. Anti-Bacteria
3.4. Detection and Degradation of Pollutants
The issues of bacterial resistance have attracted considerable
concerns in the scientific community. The development of Environmental problems such as water/air pollution and food
new antibacterial agents thus becomes one great challenge.[44] safety have become growing concerns in society. The detection
The cell membrane of bacteria could be destroyed by OH· and degradation of pollutants are major and long-standing
through oxidization of the unsaturated bonds of phospholipids. problems faced by environmental scientists. Since nanozymes

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Table 1. Summary of nanozymes for various applications.

Nanozymes Activity/Mechanism Application Reference

Au POD Early cancer diagnosis, combat biofouling [14i]
Au-NH2 CAT O2 nanogenerator for US and MR dual modality imaging [31a]
Au/Pt POD Signal-amplified colorimetric immunoassay [12e]
Au/MOF POD Detect biomolecules [12f ]
Au@MIL-101@GOx POD Measure glucose and lactate [16]
V2O5-PDA-Au POD, GOx Detect biomolecules [14j]
Pt SOD, CAT Neuro protection [31b]
Biomarker assays [31c]
Reduce ROS [31d]
Fe3O4 POD, CAT Decrease cytotoxicity, delay aging and ameliorate neuro degeneration, [31e–g]
biofilm elimination, dental therapy, protein detection
Fe3O4@linoleic acid Fenton-like Single oxygen generation for cancer therapy [14b]
Fe3O4/rGO POD Kill bacteria and wound repair [28,31g,h]
Fe3O4/GOx/C(Si,GO,ZIF-8,polymers) POD Glucose detection [14e,f,31i]
CeO2 SOD, CAT Cell protection in radiation Anti-inflammation, neuro protection, [31j]
anticancer treatment, wound healing, reduced tumor growth,
CeO2-folic acid POD O2 nanogenerator for US and MR dual modality imaging, combat biofouling [14g,31h,k–n]
Mn3O4 SOD, CAT, GPx Cytoprotection in Parkinson’s disease [31h,o]
Co3O4 POD, SOD, CAT Immunohistochemistry detection [31p,q]
V2O5 GPx, POD Cell protection, combat biofouling [12b,14c,31r–t]
MoS2 POD Antibacterial, wound healing [31u]
C60 fullerene derivatives SOD Protection against xenobiotic-induced oxidative stress, neuro protection, [31h,v]
improving the oxidative stability of polymers at elevated temperatures
Graphene quantum dots POD Wound disinfection [31i]
Prussian blue (KFe3+[Fe2+(CN)6]) POD, CAT, SOD Protection against oxidative stress [31w]

catalytic H2O2 to produce OH· that attacks organic compounds, by nanoenzymes via a partial electron exchange interaction
leading to the formation of intermediate species, further to CO2 (Figure 4a).[49] The produced OH· oxidizes the substrate, leading
and H2O, nanozyme-based methods have been proved to be to the formation of intermediate species, which produces a
simple yet powerful for detection and degradation of pollutants typical color, binds to the dimeric product, or further oxidizes
such as dyes (methylene blue, rhodamine), lignin, and other to CO2, H2O, and inorganic salts.[50] Unlike the Fenton reac-
organic compounds (phenol, benzene, anilines, chlorophenols, tion mechanism, some nanozymes may exhibit peroxidase-like
melamine) containing in wastes and food. The way of gener- activity through an electron transfer mechanism (Figure 4b).[48b]
ating hydroxyl radicals includes chemical, electrochemical, son- In the whole process, NPs act as a mediator to transfer electron
ochemical, and photochemical processes. Metal, especially iron, to facilitate the reaction between H2O2 and substrate. The sub-
is by far the most commonly used as active phase and a wide strate could be oxidized directly without producing hydroxyl
range of materials have been tested as supports or catalysts the radicals.[48b,51] Upon localized surface plasmon resonance excita-
mselves.[10,14b,15,29,31s,47] tion, hot electrons are generated and injected into the molecular
orbitals of H2O2, activating and decomposing H2O2 into OH·
and OH− anion (Figure 4c).[52] Meanwhile, the generated holes
4. Catalytic Mechanism and Theoretical Study can be scavenged by OH− anions, oxidation of water, or additional
electron donors. The recombination of hot electrons and holes
4.1. Peroxidase-Like Activity can be effectively prohibited by scavenging of holes, contributing
fast cleavage of H2O2 and increasing the reaction rate.[52,53]
In general, the catalytic pathways for peroxidase-like activity
can be divided into ROS production and electron transfer
process.[48] It has been well recognized that the activity of 4.2. Oxidase-Like Activity
peroxidase-like nanozyme may be induced by the Fenton or
Fenton-like reactions.[31e] H2O2 can be adsorbed onto the sur- Many studies have shown that oxidase mimic NPs used in
face of nanozyme first, followed by the breaking up of OO colorimetric detection of kinds of substrates could catalyti-
bond of H2O2 into double hydroxyl radicals that are stabilized cally oxidize substrates with O2, producing oxidized substrate

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Figure 4. Catalytic mechanism and theoretical studies of nanozymes. a) Proposed catalytic bromination mechanism of the CeO2-x nanorods. Reproduced
with permission.[49b] Copyright 2017, Wiley-VCH. b) Mechanism of peroxidase-like activity of WSe2 nanosheets.[48b] Copyright 2017, The Royal Society of
Chemistry. c) Proposed mechanism for localized surface plasmon resonance enhanced enzyme-like performance of AuNPs. Reproduced with permission.[52]
Copyright 2017, Wiley-VCH. d) Proposed mechanism of O2·− dismutation by C3. Reproduced with permission.[31j] Copyright 2004, Elsevier. e) Mechanism
for the oxidation of hydrogen peroxide and the regeneration. Reproduced with permission.[54] Copyright 2011, The Royal Society of Chemistry. f) The
predicted mechanisms for the pH-switchable peroxidase-like and catalase-like activities of the metals. Reproduced with permission.[57] Copyright 2015,
Elsevier. g) Schematic representation of the qualitative Sabatier principle. h) Ammonia synthesis rate as a function of nitrogen adsorption energy and
N2 dissociation barrier. i) Rate shown as a function of the nitrogen adsorption energy. (g)–(i) Reproduced with permission.[60] Copyright 2015, Elsevier.

and H2O2.[31w,34] The mechanisms depend on the structures of also depends on the structure of NPs. The mechanism of
both substrates and NPs. nanoceria catalase-like activity has been proposed, which
is similar to its SOD-like activity involving the redox cycle
between Ce3+ and Ce4+ oxidation states and oxygen vacan-
4.3. Superoxide Dismutase-Like Activity cies. The OO bond of adsorbed H2O2 dissociates with the
assistance of proton, leading to the leave of H2O from the
Although many NPs show similar SOD mimic activity and turn surface.[54]
O2·− radical to H2O2 and O2, the mechanisms are actually struc-
ture dependent. For instance, the electron-deficient regions of
the C60[C(COOH)2]3 nanozymes first attract the substrate anions 4.5. Theoretical Study of the Catalytic Mechanism
(i.e., O2·−) electrostatically to the surface of the nanozyme,
followed by further dismutation of the substrate (Figure 4d).[31j] Gao’s group carried out a series of theoretical studies on the
The protons from the carboxyl groups facilitated the entire pro- catalytic mechanism based on density functional theory (DFT)
cess. The activity of CeO2 is derived from a fraction of Ce3+ ions calculations. The peroxidase-like activity of nanocarbon oxides
(Figure 4e).[54] The defects, compensated by oxygen vacancies, was reported where the carboxyl groups (COOH) were sug-
are enriched at the surface of NPs. A dismutation mechanism gested to oxidize into peroxycarboxyl groups (COOOH),
of nanoceria involving the redox cycle between Ce3+ and Ce4+ which homolytically cleave and generate OH· radicals and oxi-
oxidation states was proposed. The superoxide adsorbed at the dize 3,3′,5,5′-tetramethylbenzidine (TMB) into oxTMB.[56] The
oxygen vacancies reacts with protons, leading to the leave of mechanisms for both activities and their pH-switchability were
H2O2 from the surface, which is similar to the mechanism of studied for metals (e.g., Au, Ag, Pd, and Pt) (Figure 4f).[57] It was
Fe- and Mn-SOD mimics.[55] suggested that H2O2 first breaks the OO, subsequently two
OH· subsequenform H2O and O·. The highly oxidizing O· will
readily attract hydrogen atoms from organic substrates. In basic
4.4. Catalase-Like Activity conditions the preadsorbed OH acts as active site, triggering the
acid-like decomposition and leading to the formation of O2.[44]
Many NPs show catalase-like activity. With the help of catalase They examined the catalytic reaction mechanisms responsible
mimic, H2O2 turns to H2O and O2. The reaction mechanism for the peroxidase, catalase, oxidase, and SOD-mimicking

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activities of N-doped rGO (N-rGO). They revealed that N-rGO information has been gathered about the detailed catalytic
selectively activated H2O2 rather than O2 and ·O2− by forming mechanism of the nanozymes. It becomes important to shift
and stabilizing radical oxygen species adjacent to the N sites nanozymes from currently an empirical science to one built
of N-rGO. The radical oxygen species then oxidized peroxi- on theory and solid foundation, which requires the collabora-
dase substrates, endowing N-rGO with peroxidase-mimicking tion of scientists from multidisciplinary areas. Moreover, if
activity and negligible catalase, SOD, and oxidase-mimicking we could build a database for the relationship between the
activities.[3e] The reaction mechanism for the SOD activities of structure of nanozymes and the catalytic performance, then
noble metal was suggested as follows. The protonation of O2· nanozymes with desired functions would be more easily
and the adsorption and rearrangement of HO2·onto the metal synthesized, just like the enzyme protein synthesis in living
surface were proposed to be the most relevant factors. Since systems.
O2·is a Bronsted base with a pKb of 9.12, it can be readily proto-
nated by water to form HO2·.[58]
5.2. Challenges in Catalytic Applications

4.6. General Principles from Heterogenic Catalysis The high stability and catalytic activity of nanozymes provide
easy access to prepare catalysts and medicine for a broadened
In essential nanozymes’ reaction is a type of surface reac- scope of applications. However, the selectivity and activity of
tion, and the general principles from heterogenic catalysis nanozymes need to be promoted and the biocompatibility
are helpful for understanding the behavior of nanozymes, is a challenging problem we have to face. Rational design of
including energy trends in catalysis, activity, and selectivity nanozymes on the basis of the deep understanding of the struc-
maps, and the electronic factor in heterogeneous catalysis ture and catalytic mechanism is necessary to resolve these limi-
(d-band model).[59] tations. In this regard, controlling the morphology and facets of
It has been found that the adsorption energies of different NPs, modification and design of integrated nanozymes mimi­
surface intermediates are proportional to each other, although cking the active site and structure of natural enzymes have
the surface intermediates are bound to the surface by the same been proved highly effective.
atoms. Such scaling is not unique for transition metal surface.
Actually, the scaling between electronically similar adsorbates
for metal-terminated surface of more complex systems also 5.3. Challenges in Biocompatibility
exists. Transition state energies also correlate with adsorption
energies. It is extremely important to understand heteroge- Considering the intersection of catalytic chemistry and bio-
neous catalysis based on the scaling between transition state medicine, the further clinical application of nanozymes
energies and adsorption energies. strongly depends on their biocompatibility and therapeutic
The Sabatier principle is one of the oldest qualitative con- biosafety. It must meet safety and efficacy requirements
cepts in catalysis stating that given a reaction, the catalytic strictly.[62] The dynamics and the ultimate fates of nanozymes
activity follows a volcano-shaped curve (Figure 4g).[60] Only should be systematically studied at different stages of treat-
an intermediate binding on the surface of a catalyst will ment, including pharmacokinetics, absorption, distribu-
result in a reasonably catalyst. According to the transition tion, metabolism, duration of therapeutic effect, excretion,
state scaling relations, the relation between the rate of activa- and toxicity of nanozyme.[63] Biodistribution studies showed
tion and the rate of formation of the products is monotonic that without targeting molecules, nanozymes would accu-
(Figure 4h,i).[60] mulate mainly in the liver, lung, and spleen. It is necessary
The simple d-band model assumed that the extra interaction to endow nanozymes with targeting ability by surface modi-
with the transition metal d electrons has contribution to the fication for enhanced therapeutic efficacy and mitigatory
adsorption energy. It provided an understanding of the scaling cytotoxicity.[63b,64]
relations between adsorption energy and activation energy,
which determine the catalytic activity.[61]
5.4. Challenges in Theoretical Studies

5. Summary and Outlook The importance of computational research for a better under-
standing of the electronic structures and catalytic mecha-
We have highlighted the progress made in the development of nisms of nanozymes is being recognized. The significance
nanozymes and their applications in diverse fields over the past of theoretical studies is that it complements experimental
decade. This field is highly dynamic and is believed to provide research and directs experimental studies. Due to the effi-
exciting challenges and opportunities in the future. ciency and accuracy, DFT investigation has dominated in
the past few years in predicting the geometry and energy
of the nanomaterials. However, more theoretical methods
5.1. Challenges in the Optimization of Structure and Function should be introduced into this field due to the complexity of
nanozymes. Further theoretical work needs to be carried out
Although various methods have been developed to fabri- due to its importance and the limitation of theoretical reports
cate nanozymes with structure precisely controlled, little in this field.

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Acknowledgements [10] G. Bystrzejewska-Piotrowska, J. Golimowski, P. L. Urban, Waste

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