APL Materials EDITORIAL [Link].

org/aip/apm

Nanozymes for biomedical applications

Cite as: APL Mater. 12, 100401 (2024); doi: 10.1063/5.0237766
Submitted: 6 September 2024 • Accepted: 16 September 2024 •
Published Online: 3 October 2024

Xin Wang,1 Yutong Fang,1,2 and Ying-Wei Yang1,a)

AFFILIATIONS
1
College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
2
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

a)
Author to whom correspondence should be addressed: ywyang@[Link]

ABSTRACT
Nanozymes, defined as nanomaterials with intrinsic enzymatic properties, have evoked fundamental new science and offer new paradigm
technologies for developing multifunctional diagnostic and therapeutic nanoplatforms. To comprehend the field of nanozymes, this Edi-
torial briefly reviews the significant developments in their design and fabrication, highlighting existing challenges and future perspectives,
promoting the further flourishing development of nanozyme-based materials toward superior biomedical applications.
[Link]

I. INTRODUCTION ferromagnetic (Fe3 O4 ) nanoparticles with peroxidase (POD)-

mimicking activity,4 inspiring a surge of nanozymatic materi-
Enzyme engineering, which mainly encompasses the prepara- als characterized by numerous distinctive advantages, including
tion, immobilization, modification, and transformation of enzymes, low cost, high stability, mass production potential, and multi-
emerged as a distinct field in the 1960s in response to the growing functionality. The term “nanozymes” was formally defined by Wei
demand for enzymatic applications. Initially, enzymes were predom- and Wang in 2013 to encompass a broader range of nanomaterial-
inantly sourced from the tissues or cells of plants, animals, and based artificial enzymes, which include diverse compositions,
micro-organisms. These natural enzymes, primarily protein-based topologies, and morphologies.5 Nanozymes integrate theories and
with a minority of catalytic nucleic acids, exhibit remarkable cat- methodologies from nanotechnology, chemistry, biomedicine, and
alytic efficiency and substrate specificity under mild physiological other interdisciplinary fields, earning recognition as one of the
conditions by lowering the activation energy of biochemical reac- top ten emerging technologies in chemistry by the Interna-
tions. These reactions are foundational to essential biological pro- tional Union of Pure and Applied Chemistry (IUPAC) in 2022.6,7
cesses, such as metabolic pathways, signaling, DNA replication and To date, over 1200 distinct types of nanozymes have been
repair, and cell division. Over the past decades, significant advance- reported to replace natural enzymes across various applications,
ments in enzymatic reactions have been achieved across various from environmental monitoring to biomedical diagnostics and
fields, including biotechnology, medicine, chemistry, and indus- therapeutics.
trial applications. However, the widespread utilization of natural Numerous reviews have addressed various facets of nanozymes.
enzymes is hindered by some inherent limitations, such as complex For instance, Liang and co-workers compiled fabrication strategies
preparation procedures, high purification costs, unstable catalytic for nanozymes, categorizing them based on metal-based, metal-free,
activity, intrinsic environmental sensitivity, and poor recyclability. and metal–organic framework materials.8 Furthermore, the prepa-
Consequently, there is an urgent need to develop alternative artifi- ration processes of nanozymes can be classified into two primary
cial enzymes to overcome these limitations associated with natural categories: (1) immobilization, loading, or entrapment of natural
catalysts. enzymes or catalytic groups onto nanosupports or nanocarriers9
Nanozymes, nanomaterials exhibiting intrinsic enzymatic and (2) direct preparation of nanomaterials with inherent enzymatic
properties, have gained substantial attention over the past few properties. In addition, Qu and co-workers provided a classifica-
decades.1,2 The first nanozyme was developed by Scrimin and tion of nanozymes based on the types of natural enzyme-mimicking
co-workers in 2004 via anchoring triazacyclononane/Zn(II) com- activities, distinguishing between the oxidoreductase family [includ-
plexes on gold nanoparticles (NPs) to mimic ribonuclease (RNase).3 ing POD, catalase (CAT), superoxide dismutase (SOD), oxidase
Subsequently, in 2007, Yan, Perrett, and co-workers identified (OXD), glucose oxidase (GOx), and glutathione peroxidase (GPx)]

APL Mater. 12, 100401 (2024); doi: 10.1063/5.0237766 12, 100401-1

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 APL Materials EDITORIAL [Link]/aip/apm

to induce the simultaneous precipitation of one or more compo-

nents from a precursor salt solution. This method offers signifi-
cant versatility for the large-scale fabrication of both homogeneous
and hybrid metal-based nanozymes, making it particularly suitable
for synthesizing alloy nanozymes.2,12 The sol-gel method relies on
gelation polycondensation reactions followed by heat treatment to
create a stable gel system. It is renowned for its versatility in engi-
neering nanozymes, enabling precise modulation of their shape,
size, composition, and porosity. Thermal decomposition involves
the heating-induced breakdown of precursor metal compounds,
resulting in nanozymes with specific surface properties and cat-
alytic performances. This method is often favored for synthesizing
various metal oxides, sulfides, and carbon-based materials.13 The
microwave-assisted method, based on dipole rotation and ionic
conduction mechanisms, is recognized for its rapid and uniform
heat transfer across samples. This technique accelerates reaction
kinetics and allows for the precise tailoring of the physicochemical
properties of organic–inorganic hybrid nanozymes, including car-
bides, nitrides, sulfides, oxides, and porous organic frameworks.14
Despite the contributions of these methods to the advancement
of nanozyme research, the catalytic performance of nanozymes
FIG. 1. Schematic illustration of nanozymes for biomedical applications. is often limited by uncertain active sites and surface defects. To
address these challenges, single-atom nanozymes (SAzymes) have
emerged as a promising subfield.15 Characterized by well-defined
structures and singular active sites, SAzymes exhibit remarkable
and the hydrolase family (such as phosphatase, protease, esterase, sil- catalytic activity due to their fully exposed unsaturated coordina-
icatein, and nuclease).10 The most important feature of nanozymes is tion of active atoms. This unique feature bridges the gap between
their ability to merge catalytic activity with the unique physicochem- natural enzymes and traditional nanozymes. For instance, Dong,
ical properties of nanomaterials, thereby revitalizing traditional arti- Wang, and co-workers pioneered the development of a carbon
ficial enzymes and broadening the scope of enzyme engineering nanoframe-confined axial N-coordinated single-atom Fe (FeN5
technologies. SA/CNF) as an oxidase mimic, utilizing a bottom-up method to
This Editorial seeks to bring snapshots of the most pivotal generate reactive oxygen species (ROS) for antibacterial applica-
advancements in the design and synthesis of nanozymes, typical tions in vitro and in vivo.15 Li and co-workers highlighted recent
types and underlying mechanisms, diverse biomedical applications, progress in SAzymes, focusing on their synthesis, mechanisms,
and the persistent challenges and key opportunities within this field and notable biological applications. Furthermore, recent important
(Fig. 1). It is crucial to emphasize that the studies highlighted herein reviews have addressed the rational design and modulation of the
do not encapsulate the entirety of nanozyme research, given the biocatalytic properties of SAzymes, presenting promising oppor-
rapid evolution and extensive range of applications. tunities to revolutionize traditional nanomedicine efficiently and
safely.16–18
In addition to the synthetic methodologies, effectively modu-
II. SYNTHESIS AND MANIPULATION OF NANOZYMES lating the catalytic activities of nanozymes remains another critical
With the development of materials science and nanomedicine, issue for their engineering in biomedical applications. The catalytic
various kinds of methods have been employed to prepare activity of nanozymes is influenced by various internal and exter-
nanozymes, such as hydro-/solvothermal processes, co- nal factors. Internal factors include composition, size, morphology,
precipitation, sol-gel techniques, thermal decomposition, and and surface modifications, and external factors involve pH, ionic
microwave-assisted methods. These approaches enable precise strength, temperature, light, ultrasound, and both electronic and
control over the diverse characteristics and unique advantages of magnetic fields.12
nanozymes for specific applications.7
Hydro-/solvothermal methods are widely employed to pre-
pare metal- and metal oxide-based nanozymes. This single-step, III. CATALYTIC PERFORMANCES
low-energy technique facilitates the synthesis of nanozymes in aque- AND MECHANISM OF NANOZYMES
ous solutions under specific temperature and pressure conditions.11 The exploration of catalytic mechanisms plays a crucial role
It is particularly effective for modulating the components and in the rational design and precise regulation of nanozymes, sig-
structures of nanozymes to meet practical demands by optimizing nificantly influencing their physicochemical characteristics, such as
reaction conditions, such as time, temperature, and precursor con- stability, specificity, and sensitivity, which are vital for a wide range
centration. This method is especially advantageous for producing of biomedical applications. To date, nanozymes have successfully
nanozymes with high crystallinity and uniform size distribution. mimicked numerous natural enzymes, including POD, CAT, SOD,
The co-precipitation method involves the addition of a precipitant OXD, GOx, sulfite oxidase, GPx, protease, esterase, and nuclease.

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The typical Michaelis–Menten constant (Km ) and maximum reac- D. SOD-like activity
tion rate (Vmax ) of various nanozymes have been comprehensively SOD-like nanozymes catalyze the dismutation of O2 − into
summarized in the literature.19 Most nanozymes effectively simulate H2 O2 and O2 under mildly alkaline conditions (pH 8–9), as rep-
the activities of oxidoreductases, including POD, CAT, OXD, and resented by the equation 2O2 − + 2H+ = H2 O2 + O2 . A variety
SOD, whereas a smaller subset exhibits catalytic capabilities akin to of SOD-like nanozymes, including Mn3 O4 , Co3 O4 , CeO2 , and Au,
hydrolases and other enzyme classes. have emerged as promising nanoplatforms for antioxidant and anti-
aging applications. Among these, cerium-based nanozymes, which
A. POD-like activity undergo a redox cycle between Ce3+ and Ce4+ , exemplify mate-
The pioneering discovery of Fe3 O4 nanoparticles with intrin- rials that exhibit multiple enzymatic activities, including SOD-like
sic POD-like activity, which catalyzes substrate oxidation through properties. Gao and co-workers elucidated a two-step catalytic cycle
the consumption of hydrogen peroxide (H2 O2 ), has inspired the mechanism involving the chemisorption of two HOO⋅ on the surface
design and discovery of various nanomaterials as POD mimics. of CeO2 . They further revealed that the effective catalytic activity is
These involve metal oxides, carbon-based materials, metals, metal determined by the energy of newly generated, short-lived intermedi-
sulfides, and composites derived from these materials. The POD- ate species situated at the midpoint of the redox potentials for both
like catalytic reactions occur both on the surface and within the half-reactions.22
nanozymes and involve two primary mechanisms: Fenton-like reac-
tions that generate hydroxyl radicals (⋅OH) and electron reservoir E. Multi-enzymatic nanozymes
mechanisms that facilitate electron transfection.
With the burgeoning development of nanotechnology, multi-
enzymatic nanozymes that exhibit more than one enzyme-
B. CAT-like activity mimicking activity have garnered considerable attention in recent
CAT-like nanozymes, which catalyze the decomposition of years.23 For example, AuNPs simultaneously demonstrate GOx-
H2 O2 into water (H2 O) and oxygen (O2 ), play a vital role in regu- and POD-like activities, and CeO2 -based nanozymes exhibit
lating ROS, thereby protecting cells from oxidative stress and alle- SOD-mimicking activity at higher Ce3+ /Ce4+ ratios and POD- and
viating hypoxic conditions.20 In general, the catalytic mechanisms CAT-mimicking activities at lower ratios. These multi-enzymatic
of CAT-like nanozymes can be classified into three categories: (1) activities hold massive potential for mimicking the synergistic
an acid-like dissociative mechanism that involves the heterogeneous effects, cascade reactions, and stimuli responsiveness of natural
cleavage of the H–O bond in H2 O2 , resulting in the combination enzymes by reducing diffusion barriers and enhancing the local
of the released proton with another H2 O2 molecule to generate concentrations of intermediates.
two H2 O molecules; (2) a base-like dissociative mechanism that
cleaves the O–O bond to produce two ⋅OH, ultimately yielding H2 O
IV. BIOMEDICAL APPLICATIONS
and O2 through a series of intermediates and transition states; and
(3) a bihydrogen peroxide associative mechanism triggered by the Nanozymes are becoming formidable alternatives to natural
co-adsorption of two H2 O2 molecules. enzymes, owing to their unique advantages, particularly the long-
lasting and adjustable enzymatic activities, as well as their favorable
biocompatibility. Recent advancements in nanozyme technology
C. OXD-like activity
have facilitated sophisticated biomedical applications, encompass-
OXD-like nanozymes, represented by mimics of GOx, sulfite ing areas such as sensing and imaging, microbial infections, inflam-
oxidase, polyphenol oxidase, and cytochrome c oxidase, catalyze the mation, tumors, neurodegenerative diseases, and other medical
oxidation of organic substrates (electron donors) using molecular conditions.
O2 as the electron acceptor under ambient conditions, often pro-
ducing H2 O2 , H2 O, or superoxide anion (O2 − ).21 Depending on
the type of electron donors, OXD-like nanozymes can be catego- A. Biosensing
rized into various groups, including amino, CH–OH, Ph–OH, and A growing number of nanozymes have been applied to biosens-
sulfur-containing groups, as well as ferrous ions. For example, gold ing, particularly for the detection of physiological indicators (e.g.,
nanoparticles (AuNPs) were first reported in 2004 to catalyze the blood glucose, glutathione, phosphatase, uric acid, and ROS) and
oxidation of glucose (which contains CH–OH bonds) into gluconic disease biomarkers (e.g., carcinoembryonic antigen and prostate-
acid and H2 O2 by facilitating the transfer of hydride from glucose specific antigen). Various detection techniques have been developed,
to AuNPs, ultimately combining with O2 . This discovery has led transitioning from in vitro assays to in vivo therapies, including elec-
to numerous reports of nanomaterials, such as Au, Pt, Ru, Ir, Pd, trochemical methods, colorimetric assays, luminescence, fluores-
Rh, and their alloys, exhibiting GOx-mimicking properties. Other cence, chemiluminescence, photoelectrochemical sensing, enzyme-
widely used OXD-like nanozymes, such as MoO3 nanoparticles and linked immunosorbent assays (ELISAs), and clustered regularly
Pd@Ir nanosheets, catalyze the oxidation of toxic sulfite to sulfate, interspaced short palindromic repeats (CRISPR) assays. Dong and
demonstrating the significant potential for treating sulfite oxidase co-workers reviewed the role of nanozymes as probes in biosens-
deficiency. In addition, a few other engineered nanomaterials with ing and immunoassays, highlighting their significance in analytical
OXD-mimicking properties were developed, such as CuO and citric chemistry.24 In addition, Stevens and co-workers emphasized the
acid-based carbon dots, providing an excellent opportunity for the unique capabilities of nanozyme-assisted platforms for clinical mon-
acquisition of desired nanozymes. itoring and disease diagnosis, particularly in point-of-care settings,

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 APL Materials EDITORIAL [Link]/aip/apm

where these methods outperform conventional assays in terms of 3. Antifungal applications

precision, cost-effectiveness, and time efficiency.25 Compared with bacteria and viruses, enhancing antifungal effi-
cacy represents a significant challenge, mainly due to the unique
B. Anti-infection structural characteristics of fungi, such as their thicker cell walls
Infectious diseases caused by various micro-organisms, includ- and hyphal formations.28 Nanozymes are promising for treating
ing bacteria, viruses, and fungi, pose significant global health chal- fungal infections, especially when combined with other physico-
lenges. Although the introduction of antibiotics has markedly inhib- chemical properties, such as drug delivery, magnetic targeting, or
ited these pathogens, the misuse of antibiotics has resulted in the natural peptide-like activities. As a representative example, Gao
emergence of antibiotic resistance. Nanozymes are being explored and co-workers designed a dual-nanozyme with phospholipase
as promising broad-spectrum antimicrobial agents, circumventing C- and POD-like activities for a cascade antifungal treatment tar-
the limitations associated with traditional antibiotics and natural geting Candida albicans.29 This represents an innovative approach
enzymes.26 to facilitating the targeting and capture of the pathogen, leading to
wall disruption, lipid peroxidation, and ferroptosis.

1. Antibacterial applications
C. Antioxidation for treatment
The antimicrobial mechanisms of nanozymes can be cate-
of various pathological disorders
gorized into two primary mechanisms: (1) oxidative damage to
bacterial membranes and biofilms through the mimicking oxi- In addition to significant progress in anti-infection applica-
doreductases to produce ROS, including O2 ⋅– , ⋅OH, 1 O2 , HOO⋅, tions, nanozymes also play a crucial role in treating several redox-
hypochlorous acid, and nitrogen radicals, and (2) the cleavage of regulated diseases in which ROS plays a primary and critical role
phosphate, amide, and glycosidic bonds in biofilms via hydrolase- in intracellular signaling. Excessive ROS can oxidize biological
like activity. These distinctive mechanisms significantly reduce the macromolecules and disrupt intracellular signaling, leading to var-
probability of bacterial resistance, presenting a promising avenue for ious pathological conditions, such as acute injury, inflammation,
enhancing antibacterial efficacy. ischemia-reperfusion, cancer, neurodegeneration, atherosclerosis,
arthritis, and kidney disorders. The versatility of nanozymes has
been demonstrated as effective analogs of endogenous antioxidant
2. Antiviral applications enzymes for regulating intracellular homeostasis.30
For instance, ultrathin graphitic carbon nitride anchored
Moreover, various nanozyme-based combined antimicro-
with AuNPs exhibits POD-like activity for bacterial killing and
bial agents have been developed. Among them, multi-enzymatic
wound disinfection. Ceria NPs with CAT- and SOD-like activ-
nanozymes are particularly promising for achieving synergistic
ities help suppress inflammatory reactions and prevent hepatic
or cascade reactions that enhance therapeutic effects. For exam-
ischemia-reperfusion injury. In addition, MnO2 nanosheets loaded
ple, combinations of GOx/POD, SOD/CAT, POD/SOD/CAT, and
with upconversion NPs display CAT-like activity for imaging-
POD/CAT/OXD/SOD mimicking activities have demonstrated the
guided oxygen-elevated synergistic antitumor effects. Prussian blue
capability to simultaneously eliminate bacteria, reduce oxidative
nanozymes, exhibiting POD-, CAT-, and SOD-like activities, effec-
stress, alleviate hypoxia, and facilitate glucose oxidation. Recent
tively scavenge ROS and alleviate neurodegeneration, such as in
comprehensive reviews have summarized advancements in antibac-
Parkinson’s disease. Furthermore, selenium-loaded metal–organic
terial nanozymes from multiple perspectives, including design,
framework-based cascade nanozymes with SOD- and GPx-like
mechanism, and applications.26 In addition to their enzymatic
activities have shown promise in alleviating oxidative stress and
activities, the unique physicochemical properties of nanozymes
atherosclerosis.
offer additional possibilities for synergistic antimicrobial treatments.
Properties such as the plasmonic effect, photocatalysis, porosity, and
surface modifications can enhance photothermal therapy, photody-
namic therapy, and drug delivery, thereby significantly improving V. FUTURE PERSPECTIVE: CHALLENGES
antibacterial performance. On the other hand, various nanozymes, AND OPPORTUNITIES
including SAzymes, have been developed for broad-spectrum antivi- Although nanozymes have been extensively studied in various
ral and antifungal applications due to their tunable catalytic and biocatalytic reactions and have addressed some intrinsic limitations
surface properties.27 The antiviral efficacy of nanozymes can be of natural enzymes, substantial challenges remain in the rational
divided into two primary approaches based on their interactions design of multifunctional nanozyme-based theranostic platforms.
with viruses.26 One strategy involves the direct disruption of viral (1) Although numerous methods for synthesizing nanozymes have
structures, for instance, catalyzing lipid peroxidation through Fe3 O4 been developed, there is an urgent need for novel controllable, envi-
POD-like nanozymes, triggering a virus-scavenging mechanism via ronmentally friendly, and large-scale production techniques. Such
virus-modified nanozymes, and targeting the peptide bonds of advancements are essential for extending the application scope of
viral coat proteins using Cu1.96 S-protease nanozymes. The other nanozymes, particularly in achieving multi-enzymatic catalytic per-
approach is indirectly regulating the intracellular microenvironment formance for synergistic therapies. (2) There is an urgent need to
of host cells, particularly through the modulation of ROS levels. For precisely modulate the catalytic properties of nanozymes, includ-
example, V2 O5 -GPx nanozymes can mitigate viral pathogenicity via ing substrate specificity and stimuli-responsive characteristics tai-
decreasing intracellular ROS. lored for specific abnormal physiological indicators in precision

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 APL Materials EDITORIAL [Link]/aip/apm

4
medicine. (3) A comprehensive understanding of how the com- L. Gao, J. Zhuang, L. Nie, J. Zhang, Y. Zhang, N. Gu, T. Wang, J. Feng, D.
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5
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7
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10
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12
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15
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AUTHOR DECLARATIONS
36(21), 2313406 (2024).
17
Author Contributions J. Xi, H. S. Jung, Y. Xu, F. Xiao, J. W. Bae, and S. Wang, “Synthesis strategies,
catalytic applications, and performance regulation of single-atom catalysts,” Adv.
Xin Wang: Conceptualization (equal); Writing – original draft Funct. Mater. 31(12), 2008318 (2021).
18
(lead). Yutong Fang: Writing – original draft (supporting). Ying- B. Chang, L. Zhang, S. Wu, Z. Sun, and Z. Cheng, “Engineering single-atom
Wei Yang: Conceptualization (equal); Supervision (lead); Writing – catalysts toward biomedical applications,” Chem. Soc. Rev. 51(9), 3688–3734
review & editing (lead). (2022).
19
L. Yang, S. Dong, S. Gai, D. Yang, H. Ding, L. Feng, G. Yang, Z. Rehman, and
P. Yang, “Deep insight of design, mechanism, and cancer theranostic strategy of
DATA AVAILABILITY nanozymes,” Nano-Micro Lett. 16(1), 28 (2023).
20
D. Xu, L. Wu, H. Yao, and L. Zhao, “Catalase-like nanozymes: Classification,
Data sharing is not applicable to this article as no new data were catalytic mechanisms, and their applications,” Small 18(37), e2203400 (2022).
created or analyzed in this study. 21
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