The age of bioinspired molybdenum‐involved nanozymes: Synthesis, catalytic mechanisms, and biomedical applications

Molybdenum (Mo), as a nontoxic and low‐cost transition metal, has been employed for synthesis of various Mo‐based nanomaterials with unique structures and physicochemical features to achieve various properties. Especially, bioinspired Mo‐based nanomaterials show great potential for the construction of novel nanozyme catalysts due to their variable oxidation states. Overcoming drawbacks of natural enzymes, bioinspired Mo‐based nanozymes not only provide effective catalytic sites or multivalent elements to mimic natural enzymes, but also present multiple functions for interfacing with various biomicroenvironments. Construction of vast Mo‐based nanozymes has attracted enormous interest in biomedicine. Exogenous/endogenous stimuli enable the user to tailor the catalytic activities of Mo‐based nanozymes. Additionally, tunable physicochemical properties also have a significant influence on their enzyme‐like activity. In this review, we comprehensively summarize typical synthesis strategies, catalytic mechanism, and types of enzyme‐like activity of the bioinspired Mo‐based nanozymes. We mainly highlight desired merits of bioinspired Mo‐based nanozymes related to tunable enzyme‐like activity, stability, and multifunctionality through regulating their physicochemical properties. Furthermore, we intend to discuss their biomedical applications in biosensing and detection, oncotherapy, and combating bacteria. Finally, current challenges and future perspectives of the Mo‐based nanozymes are also proposed.


INTRODUCTION
As typical transition-metal-based nanomaterials, molybdenum (Mo)-based nanomaterials have multiphases and polyvalences. The variable oxidation states can be attributed to the existence of many easily lost single electrons in their electronic configuration. 1 The main valence states of Mo elements include Mo (0), Mo (III), Mo (IV), Mo (V), and Mo (VI). Importantly, Mo-based compounds can be converted between variable valence states, making them promising candidates for catalysts. Besides the function of catalysts, Mo-based nanomaterials have distinct physicochemical properties such as large surface area, easy surface modification, and good near-infrared (NIR) photothermal conversion efficiency, making them have broad applications in electronics, energy, sensing as well as biomedicine. [2][3][4][5] For biomedicine, Mo, an essential trace element and nutrient that is necessary for the survival of all living body from bacteria, plants, to humans, serves as a cofactor for various Mo-based enzymes such as xanthine dehydrogenase, aldehyde oxidase, sulfite oxidase (SuOx), and nitrate reductase (NRase). 6 The presence of Mo in biological systems as key component of natural enzymes catalyzing redox and oxygen transfer reactions is well established. For example, nitrogen fixation in biological system can be catalyzed by NRase, an enzyme complex containing an iron-Mo cofactor (FeMo). 7 However, just like any other natural enzymes, Mo-based enzymes are proteins, which are often unstable in storage, expensive to manufacture as well as sensitive to harsh physiochemical conditions. Nanozymes are promising substitutes for traditional enzymes with novel physicochemical properties and intrinsic enzyme-like catalytic activity. 8,9 With the rapid development of nanotechnology, biomedical applications of nanozymes have become an intensive research focus. Compared to natural enzymes, nanozymes with robust catalytic activity, low cost, high stability, and easy large-scale production can catalyze the reaction of substrates even under harsh physiological conditions. 10,11 By combining superior physicochemical properties with enzyme-like catalytic activity, nanozymes can offer multifunctional bioapplications from detection to monitoring and therapy. 10,[12][13][14] Since the discovery of Fe 3 O 4 nanoparticles (NPs) with inherent peroxidase (POD) activity by Yan et al., 15 worldwide scholars have successively revealed the enzymaticlike properties of various nanomaterials to mimic the structures and functions of natural enzymes. The enzymemimicking nanomaterials include noble metals, transition metals oxides/sulfides, carbon-based nanomaterials (e.g., graphene oxide [GO], carbon nanotubes, and carbon quantum dots [QDs]), and so on, which have been widely applied in various fields. [16][17][18] However, not all nanozymes are suitable for biological systems concerning the problem of bisosafety. As a state-of-the-art artificial enzyme, bioinspired Mo-based nanozymes have tunable enzymelike activity, high stability, and versatile functions. Based on these advantages, they can be utilized for biodetection, antioxidant, and disease therapy. Meanwhile, Mo-based nanozymes have also improved biosafety and biodegradability by tuning their physicochemical properties. 4,19 For instance, exfoliated MoS 2 nanosheets (NSs) have lower cytotoxicity than graphene and its analogues. 20,21 Decoration with Fe 3 O 4 NPs greatly facilitates high stability of MoS 2 nanoflakes (NFs) in a physiological environment. 22 MoO x NSs and NPs with high enzyme-like activity functionalized with polyethylene glycol (PEG) showed high stability in acidic microenvironments and rapid degradation and excretion at physiological pH value in vivo. 23,24 The permissible amount of Mo in circulation is 2 mg/day and complexes of Mo also showed an antidiabetic activity. 25 In consideration of their safety in biomedical applications, bioinspired Mo-based nanozymes have great development prospects in future. More importantly, due to the remarkable catalytic function for specific biochemical reactions, Mo-based nanomaterials have also been developed as promising nanozymes whose catalytic activity can be tailored by exogenous/endogenous stimuli or physicochemical properties. 26 The classes of bioinspired Mo-based nanozymes so far include molybdenum disulfide (MoS 2 ), [27][28][29] molybdenum selenide (MoSe 2 ), 30 molybdenum oxide (MoO x , 2 ≤ x ≤ 3), 31 molybdenum carbide (Mo 2 C), 32,33 and hybrid Mo-based nanomaterials (TiO 2 @MoS 2 /CoFe 2 O 4 , Au-Pd/MoS 2 , MoS 2 /GO, MoS 2 :CeO 2 , etc.). 20,[34][35][36] Hybrid Mo-based nanomaterials can integrate new functional components into their hybrid structures, and each form has its own exceptional properties. 33 MoS 2 and MoSe 2 are typical members of two-dimensional (2D) graphenelike transition metal dichalcogenides (TMDCs). 37,38 Strategies for synthesis of Mo-based nanozymes include exfoliation, 35 hydrothermal/solvothermal synthesis, 27,39 thermal decomposition, 40 and pulsed laser ablation. 41 These strategies can control the physicochemical properties of nanozymes such as phase structure, morphology, surface modification, and size, consequently affecting their enzyme-like activities. In 2014, the MoO x NPs were first reported to have oxidase (OXD)-like catalytic activity and the MoS 2 NSs were almost simultaneously reported to have intrinsic POD-like catalytic activity. 28,42 MoSe 2 and hybrid Mo-based nanozymes were then found to possess various enzyme-like activities, including POD, OXD, catalase (CAT), superoxide dismutase (SOD), and NRase. 30,31,43,44 F I G U R E 1 Schematic illustration of synthesis, classification, activity regulation, and biomedical applications of Mo-based nanozymes. Reproduced with permission. 116 Copyright 2019, American Chemical Society. Reproduced with permission. 145 Copyright 2017, The Royal Society of Chemistry To date, a number of reviews have provided an overview of nanozymes for various applications. However, a comprehensive summary of bioinspired Mo-based nanozymes in the area of biomedical applications has yet to appear. In this review, to highlight the importance of Mo-based nanozymes in the multi-interdisciplinary fields of chemistry, biology, and medicine, we systematically summarize the recent progress on the design of bioinspired Mobased nanozymes and how physicochemical effects are related to enzyme-like biocatalytic activity and the catalytic mechanisms ( Figure 1). We further discuss design strategies to exploit the relationship between physicochemical properties and the enzyme-like catalytic activity, consequently presenting the advances of Mo-based nanozymes in biomedicine for biosensing and detection, cancer therapy, and combating bacteria. Finally, current challenges and future perspectives of the bioinspired Mobased nanozymes will be highlighted. Although the current developments are in infancy, by entering the age of Mo-based nanozymes, they are expected to have more wide biomedical applications in preclinical and clinical phases.

SYNTHESIS OF MO-BASED NANOZYMES
Nanozymes, as new alternatives to natural enzymes, have gained improved catalytic performance through regulating their physicochemical properties. Synthesis of nanozymes is the precondition for investigation of their properties and applications. Although much progress in nanozyme studies has been made, it is found that their catalytic activities are lower than those of natural enzymes, which is mainly attributed to the low density of active sites and low electron mobility on nanozyme surfaces. 10,45,46 Mo-based nanozymes have variable phase structures and oxidation states, including Mo (0), Mo (III), Mo (IV), Mo (V), and Mo (VI). Far easier loss of single electrons in their electronic configuration is the main reason for their variable oxidation states. Tailored synthetic strategies can control the phase structure, oxidation states, and morphology of nanozymes, consequently influencing their enzyme-like catalytic behaviors such as substrate selectivity and multienzyme mimetic activity. [47][48][49] Therefore, the ingenious synthesis and rational design of highly efficient Mo-based nanozymes are very important. In this section, we will introduce the main strategies for the synthesis of various Mo-based nanozymes.
To date, Mo-based nanozymes have been synthesized with different compositions and phases, including MoX 2 (X = S, Se), MoO x (2 ≤ x ≤ 3), Mo 2 C as well as their hybrids. Mo-based nanozymes with diverse morphologies such as NSs, NFs, NPs, and QDs have also been fabricated. It is worth noting that surface modification of Mo-based nanozymes is often utilized to regulate their physicochemical properties such as size, surface charge, morphology,  30,116 and composition. 27,[50][51][52] In addition, different surface modifications can affect the enzyme-like catalytic activity of Mo-based nanozymes and make them highly stable and well biocompatible. A number of bottom-up and top-down approaches including exfoliation (e.g., liquid exfoliation, ultrasonic exfoliation, and chemical exfoliation), hydrothermal/solvothermal synthesis, thermal decomposition as well as pulsed laser ablation can be used to synthesize Mo-based nanozymes (Table 1). 40,41,[53][54][55] Herein, representative methods for synthesis of Mobased nanozymes are presented. Multiple MoS 2 NSs with a few layers can be extensively produced by exfoliation of bulk MoS 2 . 35,56,57 MoS 2 NFs with an average size of 390 nm can be prepared via a simple, one-step hydrothermal method. 50 MoSe 2 NFs can be prepared by liquid ultrasonic exfoliation method in a mixture of water and alcohol. 30 MoO 3-x nanodots can be fabricated via pulsed laser ablation method in MoS 2 NSs solutions. 41 In addition, multifunctional hybrid Mo-based nanozymes can also be fabricated. For instance, ternary TiO 2 @MoS 2 /CoFe 2 O 4 composite nanofibers with superior POD-like properties have been constructed via a two-step hydrothermal process. The MoS 2 NSs were first grown on TiO 2 nanofibers to act as an interfacial barrier to load ultrafine CoFe 2 O 4 NPs. 34 Zhang et al. reported that the Pt-MoO 3 hybrid nanomaterials with enhanced POD-like catalytic activity were obtained via a wet-chemical synthesis method after growth of Pt NPs on several-layered MoO 3 NSs. 58 Among these synthetic meth-ods, both hydrothermal method and liquid exfoliation strategies have distinct advantages for efficiently preparing Mo-based nanozymes with large-scale, controllable size, and facile modification. 27,43,59 In particular, liquid exfoliation strategies using surfactants, polymer solutions as well as organic solvents can not only weaken the interlayer interactions in Mo-based nanozymes for effective exfoliation but also avoid the use of explosive n-butyllithium for intercalation, which is difficult to be handled and readily introduces impurities. 60 Both of the hydrothermal method and liquid exfoliation strategies are beneficial for modulating the physiochemical properties such as phase structure and surface defects that could affect catalytic activity.
There are two important factors for improving the enzyme-like catalytic performance of Mo-based nanozymes: (i) more active sites or active centers and (ii) higher conductivity. 9,61-63 The abundant defects exposed on the surface of Mo-based nanozymes favor the generation of active sites. Up to now, much effort has been focused on the synthesis of Mo-based nanozymes with defect structures or doped elements (N, Pt, Li, etc.) to generate more active edge sites exposure for further improving the catalytic activity. 61,64 It was also reported that the thinner MoS 2 /GO composites with better conductivity had higher catalytic activity than that of thicker one. 35,65 The employment of proper synthetic strategies is the main factor in the low-cost synthesis of nanozymes with high yield and high catalytic activity, which is a significant advantage when compared with nature enzymes. Moreover, although systematically comparing the activities of Mo-based nanozymes synthesized by different methods is rare, use of the concept of specific activity for enzymology to evaluate the activity normalized as unit activity/mass of nanozymes may be feasible. Specifically, the amount of nanozyme that catalyzes 1 μmol of product per minute was used to define one nanozyme activity unit. 47,66 Overall, the synthetic methodology can influence the physicochemical properties of Mo-based nanozymes, consequently resulting in different catalytic activities.

TYPES AND MECHANISMS OF ENZYMATIC ACTIVITY OF MO-BASED NANOZYMES
Using Mo-based nanomaterials to mimic the catalytic function of natural enzymes is an interesting yet challenging task. Currently, Mo-based nanomaterials have been reported to mimic several enzymatic activities such as POD, OXD, CAT, SOD, and NRase. We discuss here the enzymatic activities and catalytic mechanisms of Mobased nanozymes.

Mo-based nanozymes with POD-like activity
PODs especially horseradish peroxidase (HRP) can catalyze peroxides such as H 2 O 2 to form reactive oxygen species (ROS) (e.g., hydroxyl radicals [ • OH]) and water. In general, POD-like nanozymes have two catalytic pathways including ROS production and electron transfer. 12,67 Most Mo-based nanozymes as prototypical TMDCs possess intrinsic POD-like activity. Various reports have demonstrated that Mo-based nanozymes as POD mimics can catalyze oxidation of diverse chromogenic substrates, such as colorless 3,3′,5,5′ tetramethylbenzidine (TMB), 2,2′azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine (OPD), 3,3′-diaminobenzidine, and dopamine into colored oxides. 50,68,69 For example, colorless TMB can be oxidized by Mo-based nanozymes into blue oxide of TMB (oxTMB) in the presence of H 2 O 2 ( Figure 2A). 50 Similar to nature enzymes, the catalytic activity of Mo-based nanozymes is affected by reaction conditions, such as pH value, concentration of substrates, temperature, and reaction time. Most Mo-based nanozymes have high catalytic activity at the temperature of 25-40 • C and the pH of 3.5-6.0. 31,[70][71][72] Their POD mimetic activity follows typical Michaelis-Menten kinetics and ping-pong catalytic mechanism, similar to natural HRP. In addition, the important kinetic parameters such as Michaelis-Menten constant (K m ) and maximum reaction velocity (V max ) have been used to evaluate catalytic efficiency of the POD-like Mo-based nanozymes. A lower K m value implies greater affinity of the enzyme toward the substrate.
The POD-like catalytic activity of MoS 2 NSs was first reported in 2014. 28 The MoS 2 NSs can catalytically oxidize TMB by H 2 O 2 to produce blue oxTMB. The catalytic activity followed the typical Michaelis-Menten kinetics and depended on temperature, pH, H 2 O 2 concentration, and reaction time. The high catalytic activity over a wide pH range (2.0-7.5) of MoS 2 NSs was applied to detect glucose in serum samples. Since then, many MoS 2 nanozymes with different surface coatings, hybridization, and heteroatom doping have been reported to possess POD-like catalytic activity. Based on the previous study, charge transfer from TMB to MoS 2 NSs is closely related to the p-type nature of few-layered MoS 2 NSs. 73 The rich active sites located at the edges of MoS 2 NSs have been thought to facilitate the electron transfer between TMB and H 2 O 2 during the catalytic reaction. In this process, TMB molecules are absorbed on the surfaces of MoS 2 NSs and promote lone-pair electrons from the amino groups of TMB to MoS 2 NSs, leading to an increase in electron density and mobility in the MoS 2 NSs surface. 74 Figure 2B). 28,62,76 Apart from MoS 2 NSs, few-layered MoSe 2 NSs also possess intrinsic POD-like activity. 30 Figure 2C). 77,78 Moreover, compared to MoS 2 and MoSe 2 , MoO x has more oxygen vacancies. 79 Thus, development of MoO x nanozymes is highly desired. Very recently, Guo et al. reported that MoO 2 NPs had POD-like activity and a higher affinity to H 2 O 2 than MoSe 2 NSs. 31 The ping-pong catalytic mechanism of MoO 2 NPs was similar to HRP. They also demonstrated that MoO 2 NPs can Single-atom (SA) nanozymes with isolated active metal centers anchored on solid supports have recently presented new breakthroughs in biocatalysis. The unique structure and coordination environment are in favor of their catalytic active sites at an atomic scale. For instance, SA Mo-based nanozyme has been constructed to possess intrinsic POD-like catalytic activity that was confirmed by experimental and theoretical studies. 82 In virtue of the . They found that the POD-like specificity was well regulated by the coordination numbers of single Mo sites. The Mo SA -N 3 -C catalyst showed exclusive POD-like behavior via a homolytic pathway, whereas Mo SA -N 2 -C and Mo SA -N 4 -C catalysts had different heterolytic pathway. The geometrical structure differences and orientation relationships of the frontier molecular orbitals toward these Mo SA -N x -C POD mimics can account for the mechanism of this coordination number-dependent enzymatic specificity. 83 In short, SA nanozymes possess excellent catalytic activity and selectivity because of the homogeneity of their active sites and geometric structure, overcoming some limitations of other nanozymes. 46 Hence, more superior SA Mo-based nanozymes are expected to be explored in the future.

Mo-based nanozymes with OXD-like activity
Natural oxidases can catalyze the oxidation of substrates into an oxidized product by reaction with O 2 . The O 2 molecule acts as an electron acceptor and can be reduced •− in some cases). The OXDmimicking activity of Mo-based nanozymes has attracted great attention. In particular, sulfite oxidase (SuOx), a Mo-dependent enzyme localizing to the intermembrane space of mitochondria, can catalyze the oxidation of sulfite (SO 3 2-) to sulfate (SO 4 2-) in the final degradation of sulfur-containing amino acids. Tremel et al. first reported that ultrasmall MoO 3 NPs acted with high similarity with the structure of active site of natural SuOx enzyme to oxidize SO 3 2to SO 4 2under physiological conditions (Figure 3A). 42 The surface of MoO 3 NPs was decorated with dopamine to anchor triphenylphosphonium ions (TPP) to form TPP-MoO 3 NPs for membrane crossing and mitochondrial targeting. Steady-state kinetics studies suggested that the active Mo 6+ of the nanozyme was firstly converted to Mo 4+ on account of sulfite oxidation, and then reverted to Mo 6+ by two-electron reduction reactions of ferricyanide. These TPP-MoO 3 NPs with good biocompatibility could specifically accumulate at mitochondria and promote the recovery of the SuOx activity of SuOx knockdown liver cells in vitro, enabling the TPP-MoO 3 NPs as a potential therapeutic agent for sulfite oxidase deficiency.
Similarly, PEGylated-MoO 3-x (P-MoO 3-x ) NPs, as another SuOx nanozyme, were also fabricated (Figure 3B). 79 Their SuOx-like activity was 12 times higher than that of bulk MoO 3 . The enhanced enzyme mimetic activity of P-MoO 3-x was ascribed to the abundant oxygen vacancies as catalytic hotspots, allowing effective SO 3 2capture ability. In this study, vitamin B1 can be irreversibly chelated by SO 3 2and has electrostatic interaction with P-MoO 3-x NPs, consequently inhibiting the SuOx activity of P-MoO 3-x NPs. Therefore, the SuOx-like P-MoO 3-x NPs have been used to detect vitamin B1 with high sensitivity through a colorimetric method.
Inspired by the SuOx mimicking of MoO 3 NPs, Chen et al. recently demonstrated that MoO 3 NPs exhibit promising OXD-like activity. 84 These NPs can catalyze the oxidation of colorless ABTS to produce a green product. As a specific target molecule of 1 O 2 , 2,2,6,6tetramethylpiperidine (TEMP) can be oxidized by 1 O 2 to be tetramethylpiperidinyloxy (TEMPO). In this study, the electron spin resonance signals of TEMPO were observed in the MoO 3 NPs solution, demonstrating the production of 1 O 2 during enzyme-like catalytic reaction. The dissolved O 2 was adsorbed onto the surface of MoO 3 NPs and then formed 1 O 2 , which finally oxidized ABTS. Acid phosphatase (ACP) could catalyze the hydrolysis of the ascorbic acid 2-phosphate (AAP) substrate to generate ascorbic acid, which can fade the color from the MoO 3 NPmediated ABTS oxidation. The MoO 3 NPs have been used as ACP detection by integrating the OXD-like property of the MoO 3 NPs with the ACP-catalyzed hydrolysis of AAP. CAT

Mo-based nanozymes with multienzyme-like activities
Inspired by cascaded reactions occurring in living organisms, researchers have attempted to design nanozymes with cascaded multiple-enzyme mimicking properties. Due to variable valence states of Mo elements, various kinds of Mo-based nanozymes can show multienzymelike activities that are usually pH dependent, and the catalytic mechanism is similar to other nanozymes like Prussian blue nanozymes and cobalt oxide nanozymes ( Figure 4). 18 Likewise, Wang and coworkers demonstrated that MoO 3-x nanodots possess favorable CAT-and SODmimicking activities owing to the efficient charge transition of Mo 5+ /Mo 6+ on the surface of nanodots. Particularly, MoO 3-x nanodots exhibited high CAT-like catalytic activity at various pH values (3.0-9.0) and the optimum catalytic activity was observed in alkaline pH 9.0. The MoO 3-x nanodots can be used as a multifunctional amyloid beta (Aβ) fibrillation modulator to alleviate Aβ- Reproduced with permission. 86 Copyright 2019, American Chemical Society mediated oxidative stress, consequently relieving amyloid aggregation-induced neurotoxicity. 41 Besides, Zheng and coworkers demonstrated that fullerene-like MoS 2 (F-MoS 2 ) NPs possess intrinsic CAT-and SOD-like activities under physiological conditions. 86 By integrating these unique properties, a self-organized cascade catalytic system was prepared, which resulted in the catalytic disproportionation of O 2 •into H 2 O 2 and then the transformation of H 2 O 2 into O 2 ( Figures 5C and 5D). The F-MoS 2 NPs were utilized to prevent human umbilical vein endothelial cells from oxidative stress caused by high-level H 2 O 2 . Based on the cascade system, F-MoS 2 NPs were combined with hyaluronic acid (HA), regulating the excessive ROS and preventing the depolymerization of HA in artificial synovial fluid. These multiple enzyme-mimicking activities equipped Mo-based nanozymes for a variety of advanced bioapplications. Furthermore, such Mo-based nanozymes may reveal insights into the ultimate form of nanozymes. However, the mechanism of the multienzymemimicking nanozymes and the optimal physiological environment of enzyme-like activity of each type of these enzymes in one multienzyme-mimicking nanozyme need to be further investigated. Whether these multiple enzymatic activities will interfere with each other or not is still unclear.

Mo-based nanozymes with NRase-like activity
Nitrate anion (NO 3 − ) is a simple, abundant, and relatively stable species, yet plays a significant role in global cycling of nitrogen, global climate change, and human health. 87 In nature, the catalytic reaction of NRase at neutral pH value using a highly-conserved Mo center ligated mainly by oxo-and thiolate groups is the most effective strategy to realize nitrate reduction reaction. The reaction catalyzed by NRase is shown in Equation 1. All NRase are Mo-dependent enzymes. So far, only a few studies have reported that nanomaterials can mimic the activity of NRase. In 2008, a peptide-mediated synthesis of CdS-Pt NPs system was demonstrated as a robust inorganic mimic for the reduction of NO 3 − to NO 2 − with activity that outperforms NRase enzyme by more than 23-fold. 88 Recently, Nakamura and coworkers reported that MoS 2 NSs can electrochemically catalyze the reduction of NO 3 − /NO 2 − to ammonia (NH 3 ) over a wide pH range (pH 3−11). 89 The pH dependence of the onset potential of the denitrification current showed that this superior activity was in virtue of the ability to cause concerted proton-electron transfer, resulting in a turnover frequency analogous to that of the extant Mo-dependent NRase. Similar to biological dissimilatory denitrification, MoS 2 NSs catalyzed NO 3 − reduction to NH 3 through NO and N 2 O intermediates, which was indicated by online differential electrochemical mass spectroscopy. These results demonstrated that the MoS 2 NSs function as a new family of bioinspired electrochemical denitrification catalysts.
The same group also synthesized an oxo-MoS x catalyst that had a hierarchical structure of assembled NSs ( Figure 6). 44

UNIQUE PROPERTIES OF MO-BASED NANOZYMES
Compared to natural enzymes, Mo-based nanozymes with different types are related to their unique physicochemical properties. Generally, to make the nanozymes have higher catalytic activity, three regulation strategies using different thoughts can be employed to promote the binding of nanozymes to substrates by (i) increasing their surface area/volume ratio, (ii) reducing the size of nanozymes, (iii) promoting the preferential exposure of active atoms with catalytic activity, and (iv) increasing the number of suspended bonds. 67,90 The core goal of these regulation strategies is to improve the exposure degree of the nanozyme active site and its similarity with the structure of active site of natural enzymes. We then describe the tunable enzyme-like activity, stability, and multifunctionality of Mo-based nanozymes based on the physicochemical property (size, morphology, doping, multicomponent synergistic effect, and surface modification)-related structurefunction relationship. This physicochemical propertyrelated structure-function relationship is closely relevant to their versatile biomedical applications.   35 The thinner MoS 2 /GO composites showed higher POD-like catalytic activity than that of thicker one because of  Figures 7A and 7B). 39 In another study, Liu et al. reported that MoO 3 nanorods exhibited higher POD-like activity than MoS 2 NSs and MoO 3 nanowires. 81 The possible reason is that when H 2 O 2 closely contacts with the MoO 3 nanorods, the electrons localized at the p orbital of the O atom in H 2 O 2 will be transferred to the d orbital of the Mo atom, leading to an intense reaction between H 2 O 2 and MoO 3 nanorods. Besides, the sufficient gap of the formed rod-like structures was favorable for collision contact between the H 2 O 2 and MoO 3 nanorods in the reaction system. These factors may promote the oxidization of H 2 O 2 efficiently. It is worth mentioning that even though the catalytic activity of Mo-based nanozymes can be regulated by their size and morphological changes, the impact of phase structures on their catalytic activity still needs to be deeply investigated. 4 Figure 7C). 91 Integrating other nanomaterials such as metals or metal oxides with Mo-based nanozymes also showed improved catalytic activity. For example, because of the synergistic catalytic effects of the three components, the MoS 2 -polypyrrole (PPy)-Pd nanotubes showed higher POD-like catalytic activity than MoS 2 , MoS 2 -PPy, PPy-Pd, and MoS 2 -Pd nanocomposite. 92 In addition, the Pt-MoO 3 hybrid nanomaterial exhibited an enhanced POD-like catalytic activity compared to the MoO 3 NSs, Pt NPs, and their physical mixture under the same conditions ( Figure 7D). 58  can be applied to selectively detect glucose. Other analogous hybrid nanozymes such as AuNPs@MoS 2 -QDs, Au-Pd/MoS 2 , MoS 2 -Pt 3 Au, and TiO 2 /MoS 2 with enhanced POD-like activity have also been developed. 20,53,93,94 Assembling carbon-based nanomaterials with Mo-based nanozymes to form hybrid nanozymes has also been investigated. As part of much effort, Weng et al. reported that a hybrid of POD-like activity of MoS 2 and graphene oxide (MoS 2 /GO) was used to detect glucose with high sensitivity through the synergistic catalytic effect. 35 The hybrid had the highest catalytic activity when compared with the two components alone and the mixture of two components and HRP. A synergetic POD-like activity was also disclosed for mixed MoS 2 QDs and graphene QDs. 95 In short, the above synergistic strategies provide inspiration for improving the catalytic activity of Mo-based nanozymes.

Surface modification
Surface modifications also contribute to modulate the catalytic performance of Mo-based nanozymes. Specifically, surface charge and exposure of active sites of nanozymes can affect the catalytic activity, specificity, and stability. At present, Mo-based nanozymes are mostly modified by organic polymers, proteins, and other biopolymers. Our group investigated the POD-like activity of PEGylated MoS 2 (PEG-MoS 2 ) NFs. The PEG-MoS 2 NSs had improved water dispersibility and stability compared to the undecorated MoS 2 , which was conducive to the catalysis velocity and affinity for TMB or H 2 O 2 , consequently improving the POD-like activity. 27 The PEGylated MoS 2 NSs have also been confirmed to possess enhanced POD-like activity. 96 Polyvinylpyrrolidone (PVP) is helpful for the construction of MoS 2 nanozyme with high yield, low cost, and good water dispersibility and biocompatibility. 97 Another typical example for affecting the enzyme-like activity of Mo-based nanozyme is surface charges. In one study, MoS 2 (SDS-MoS 2 ) NPs modified with negatively charged sodium dodecyl sulfate (SDS) possessed higher POD-like activity than that of positively charged cetyltrimethylammonium bromide. This is because the negatively charged SDS-MoS 2 NPs have strong affinity toward the positively charged TMB substrate. 51 We also compared the POD-like activities of MoS 2 NFs modified with positively charged polyethylenimine (PEI), negatively charged poly(acrylic acid) (PAA), neutrally charged PVP, and positively/negatively charged L-cysteine (Cys) (Figure 7E). 50 The PVP, PAA, and PEI modifications inhibited the catalytic activity of MoS 2 NFs, whereas the catalytic activity of the Cys-MoS 2 NFs was remarkably promoted toward TMB or ABTS substrate. This could be attributed to the enhanced charge affinity between the Cys-MoS 2 NFs and positively charged TMB, whereas the Cys on the surface of MoS 2 mainly acted as an electron transfer mediator between H 2 O 2 and negatively charged ABTS. Further work also confirmed that the Cys-MoS 2 NSs possessed enhanced POD-like activity compared with bulk MoS 2 . 75 Other biomolecules such as oxidized glutathione (GSSG) and hemin have also been used to decorate MoS 2 NSs. Both of these compounds can improve the POD-like activity of MoS 2 NSs to oxidize TMB substrate. 52,57 However, as we mentioned above, the activity of Mo-based nanozymes can sometimes be inhibited by surface modification. That is because the active sites of nanozymes could be shielded by the extra coating or modification and thus their catalytic activity decreases correspondingly. 98 Thus, more effort is still needed to develop novel methods to achieve both the colloidal stability in physiological conditions and adequate accessibility to the target substrates especially for biosensing applications.

Stability
Mo-based nanozymes show improved stability under harsh conditions such as acidic, basic, and hightemperature environments that natural enzymes cannot bear. For instance, the POD-like MoS 2 NSs showed a high catalytic activity over a wide pH range (2.0-7.5). The wide pH range could broaden the application of MoS 2 NSs in harsh environments. 28 In another work, Fe 2+ /MoO 3 as a POD-like mimic had favorable thermal stability. When reaction solution was heated to 95 • C, the POD-like activity of the nanozyme had almost no change, which can overcome the thermal instability of natural POD. The Fe 2+ /MoO 3 had good storage stability in that there was still 85% of POD-like activity when they were stored at 4 • C for 20 days. 69 In addition, the MoO 3 NPs with OXDlike property had superior catalytic performance at pH 2.5 and 70 • C. 84

Multifunctionality
Despite the enzyme-mimicking activity, Mo-based nanomaterials such as MoS 2 , MoSe 2 , and MoO 3-x also have high photothermal conversion efficiency in the near-infrared (NIR) region because of their specific electronic and optical properties. 37,100,101 In recent studies, researchers have found that both PEG-MoS 2 NFs and MoS 2 -hydrogel have good NIR photothermal conversion property and high POD-like activity. The combination of photothermal property and enzyme-like activity makes Mo-based nanomaterials an attractive platform for biomedical applications such as antibacterial and antitumor.
Mo-based nanomaterials can be utilized as a universal carrier for loading other functional molecules or reagents to create biomimetic cascade catalysis system. For example, the POD-like Mo-based nanozyme with immobilized glucose oxidase (GOx) has been constructed for glucosesensitive colorimetric detection. 81 GOx could continuously catalyze the glucose oxidation reaction and produce H 2 O 2 to support the POD-like catalytic activity of nanozyme with high selectivity and acceptable reproducibility. By integrating advantages in the selectivity of natural enzymes with controllable catalytic activity of nanozymes, Mo-based nanozymes can act as vehicles for achieving cascaded reactions. This strategy is also very similar to other biomimetic cascaded nanozymes such as iron-based nanozymes and metal-organic framework nanomaterials. 102,103 The hybrid forms of Mo-based nanozymes also endowed them with diverse functionalities. For example, the MoS 2 /Fe 3 O 4 nanozyme for colorimetric detection of perfluorooctane sulfonate can be recycled by magnetic separation owing to the assembling of Fe 3 O 4 NPs. 55 In another work, hybrid Au nanobipyramids with MoS 2 (AuNBPs@MoS 2 ) also have the POD-like activity for both anticancer therapy and cellular imaging because of the excellent two-photon luminescence of AuNBPs. 43 It deserves to be mentioned that, even though some Mo-based nanomaterials lack obvious enzyme-like activity, they can also be utilized as modulators to disperse and stabilize other artificial nanozymes. For instance, CeO 2 -PEI-MoS 2 NFs have been constructed as nanozymes for cancer photothermal therapy. The CeO 2 NPs mimicked multienzyme such as SOD, CAT, and Fenton-like catalyst properties, whereas MoS 2 NFs acted as supports of CeO 2 NPs and photothermal agents. 36 All these features indicate that Mo-based nanomaterials pave a way for the fabrication of multifunctional nanozymes for broad applications, especially in the field of biomedicine.

BIOMEDICAL APPLICATIONS OF MO-BASED NANOZYMES
Mo-based nanozymes hold great promise for biosensing and biodetection, cancer therapy, and combating bacteria ( Table 2). In the following section, we discuss the representative applications of Mo-based nanozymes.

5.1
Biosensing and biodetection  7 μM). 102,106,107 Electrochemical methods are also considered as promising strategies for highly selective, sensitive detection of H 2 O 2 . An enzyme-free electrochemical sensor was fabricated by electrochemical deposition of Au-Pt bimetallic NPs on the MoS 2 NFs surface. 54 The MoS 2 -Au/Pt nanocomposites exhibited promising catalytic activity for specific detection of H 2 O 2 . The enzyme-free electrochemical sensor had wide linear range and high sensitivity.
The MoS 2 -Au/Pt electrochemical sensor was further successfully used to detect H 2 O 2 in real serum samples. Very recently, another enzyme-free electrochemical sensor based on a porous Mo 2 C impregnated in N-doped carbon (p-Mo 2 C/NC) has been designed toward H 2 O 2 detection. The excellent biomimetic performance can be attributed to the porous Mo 2 C catalyst rather than conventionally relying on only catalyst dispersed in a porous substrate with a large reaction surface area. 32 Despite H 2 O 2 and glucose, another biomolecule cholesterol has also been sensed by Mo-based nanozymes using the colorimetric method. 72 For instance, our group fabricated GSSG-modified MoS 2 NSs (MoS 2 -GSSG NSs) with high POD-like catalytic activity, which could serve as colorimetric sensor for detection of H 2 O 2 and cholesterol. 52 The cholesterol was catalyzed by cholesterol oxidase (ChOx) in the presence of O 2 to generate H 2 O 2 , which supports the catalysis of MoS 2 -GSSG NSs to accelerate the oxidation of TMB. In addition, the Mo-based nanozymes can be used to detect reductive small biomolecules such as GSH, Cys, vitamin B1, and lipase, which can inhibit the enzyme-like activity of nanozymes in the presence of dual substrates such as TMB and H 2 O 2 ( Figure 8C). 79,94,108,109 By monitoring the degree of color fading of organic substrates, these reductive small biomolecules can be quantitatively detected.
Mo-based nanozymes have also been used to detect disease biomarkers. In particular, development of effective methods for rapid and accurate detection of cancerrelated antigens is significant for cancer diagnosis. 110,111 For example, a MoS 2 @Cu 2 O-Pt nanohybrid as an enzymemimetic label was used to construct an ultrasensitive sandwich-type electrochemical immunosensor to detect hepatitis B surface antigen. 104 As a signal amplification label, the MoS 2 @Cu 2 O-Pt nanozyme could improve the catalytic performance of immunosensor for reduction of H 2 O 2 . The prepared immunosensor exhibited high sensitivity, good reproducibility, stability, and selectivity, which may provide a powerful approach for accurate detection of other biomolecules in clinical diagnosis. Direct detection of cancer cells plays an important role in cancer diagnosis. [112][113][114] A novel MoS 2 /PtCu nanocomposite with excellent OXD-like activity has been constructed for detection of cancer cells. 74 The nanocomposites quickly catalyzed the oxidation of three common chromogenic substrates such as TMB, ABTS, and OPD in the presence of dissolved oxygen in solution, producing typical colors. On the basis of OXD-like activity of MoS 2 /PtCu and mucin 1 (MUC1) aptamer, selective binding of aptamer-conjugated MoS 2 /PtCu aptasensor (apt-MoS 2 /PtCu) on the MUC1overexpressed cells converted the recognition process into a quantitative colorimetric signal. The apt-MoS 2 /PtCu showed good sensitivity and selectivity to targeting can-   120 Copyright 2020, American Chemical Society cer cells. In another study, an ultrasensitive electrochemical circulating tumor cells (CTCs) detection strategy was developed based on reduced graphene oxide/molybdenum disulfide (rGO/MoS 2 ) NSs and immunomagnetic beads Fe 3 O 4 NPs dual enzyme mimics synergistic catalysis for signal amplification. 115 The Fe 3 O 4 NPs acted as separation and enrichment CTCs as well as enzyme mimics with rGO/MoS 2 synergistic catalysis for signal amplification in cytosensors. The rGO/MoS 2 synergistic catalysis with Fe 3 O 4 NPs showed good electrocatalytic activity toward H 2 O 2 . The proposed electrochemical biosensor could detect human breast carcinoma cells (MCF-7) down to 6 cells mL −1 with a linear range from 15 to 45 cells mL −1 at the acceptable stability condition and reproducibility. The exposure of biological toxic substances in the environment will directly or indirectly affect human health. Therefore, detections of the toxic substances are major and long-standing problems. Some metal ions (e.g., Hg 2+ , Cu 2+ , Cr 6+ , and Fe 2+ ) 40,68,116,117 and organic compounds (e.g., phenol, perfluorooctane sulfonate, trinitrotoluene, triacetone triperoxide [TATP] explosives, and carbendazim [CBZ]) in wastes and foods 53,55,69,75,118 have been detected by Mo-based nanozymes. For example, a field-portable and colorimetric sensor for the visual detection of Hg 2+ has been constructed using safe chitosan-modified MoSe 2 NSs (CS-MoSe 2 NSs) nanozyme ( Figure 8D). 116 The POD-and OXD-like activities of CS-MoSe 2 NSs were significantly promoted after the addition of Hg 2+ . That is because that the Hg 2+ can be captured by chitosan molecules and partially reduced to be Hg 0 on the surface of CS-MoSe 2 NSs. Then, in situ formed Hg 0 altered the surface properties and enhanced the binding affinity of CS-MoSe 2 NSs for TMB substrate to produce higher catalytic activities. This CS-MoSe 2 NSs-based system could be utilized to determine the Hg 2+ concentration by monitoring Hg 2+ -induced changes of the UV-Vis absorbance peaks of the blue oxTMB. More meaningfully, the Hg 2+ in real water and serum samples can be determined by integrating the CS-MoSe 2 NSs and smartphone. Moreover, MoS 2 NSs with POD-like activity were developed to detect Cu 2+ ions in drinking water because the Cu 2+ can inhibit the catalytic activity of MoS 2 NSs. The LOD value was 92 nM, which is much lower than that of Cu 2+ in drinking water. 117 Ni et al. have reported a selective fluorescent catalytic biosensor based on layered POD-like MoS 2 NSs for the detection of Fe 2+ . 119 The Fe 2+ could significantly activate MoS 2 NSs to catalyze the oxidation of OPD to generate a fluorescent product 2,3-diaminophenazine. The MoS 2 /OPD/H 2 O 2 biosensor showed a significantly enhanced fluorescence signal in the presence of Fe 2+ in real water samples.
Aside from the potentially harmful metal ions mentioned above, certain organic compounds in wastes have been detected by Mo-based nanozymes. Recently, uniform Pt 3 Au 1 NPs-decorated few-layer MoS 2 NSs were fabricated as nanozymes to detect phenol, which is a common environmental pollutant in waste water. 53 The MoS 2 -Pt 3 Au 1 nanocomposite displayed enhanced POD-like activity compared to pure MoS 2 NSs. The fast and selective colorimetric detection of phenol was based on oxidative coupling reaction of phenol and 4-aminoantipyine in the presence of H 2 O 2 as an oxidant to form pink color product. In addition, the POD-like Fe 2+ /MoO 3 NSs were constructed to visually colorimetric detect TATP explosives. 69 Because H 2 O 2 is the main product of the acidic hydrolysis of TATP explosive, Fe 2+ /MoO 3 NSs with good selectivity for H 2 O 2 can visually detect as low as 60 μM of TATP.
Mo-based nanozymes also play an important role in food safety sensors. In a very recent study, CBZ residues in tea and rice samples have been determined by an electrochemical nanozyme sensor that was coupled with machine learning for intelligent analysis. This nanozyme sensor was composed of carboxymethyl cellulose (CMC)modified graphene-like MoS 2 /multiwalled carbon nanotubes (MWCNTs) porous nanohybrid network (CMC-MWCNTs/MoS 2 ) with OXD-like activity. 118 The reciprocal of the CBZ concentration was positively correlated with the peak current, which is a typical kinetic characteristic of the biological enzyme. This electrochemical nanozyme sensor can sensitively determine CBZ with a wide linear range of 0.04-100 μM and low LOD of 7.4 nM. Thus, the proposed sensor system may play a significant role in the development of intelligently analyzing CBZ residues in agricultural products.

5.1.2
In vivo sensing and detection A number of Mo-based nanozymes for in vivo sensing have also been developed. Very recently, molybdenum-polysulfide (MoS x )-deposited nickel−iron bimetal Prussian-blue-analog-based hollow nanocages (Nanocages) with POD-, CAT-, and laccase-like activities were fabricated. 120 The POD-and CAT-like activities could scavenge ROS in cells (scavenging excess H 2 O 2 and regulate H 2 O 2 signals during oxidative stress). On the other side, the nanocages with laccase-mimicking activity have been integrated with an online sensing platform to optically detect hydrogen sulfide (H 2 S) in the brains of living rats ( Figure 8E). It was suggested that the primary mechanism of detection was H 2 S etching the reduced laccase-like activity of the nanocages, whereas the oxidation product offered the read-out signals. This finding may provide an opportunity for upgrading the design strategy of nanozyme-based in vivo detection methods. In another study, Lin et al. constructed CoMo hybrids with OXD-, POD-, and CAT-like activities by epitaxial growth of the MoS x nanosponge on Co(OH) 2 NFs surface. 121 The OXD-mimicking activity of the CoMo hybrids can catalyze the oxidization of TMB and then the produced oxTMB induced by the OXD-like catalytic reaction can selectively oxidized ascorbic acid. The proposed colorimetric strategy has been successfully utilized to measure ascorbic acid in rat brains during the cerebral calm/ischemia process.

Cancer therapy
Mo-based nanomaterials are desirable candidates for effective cancer therapy such as photodynamic therapy, photothermal therapy, chemotherapy, radiotherapy (RT), and immunotherapy. 4,122,123 Based on the catalytic properties of Mo-based nanozymes, some promising strategies have been developed for cancer therapy by modulating ROS production. In a very recent study, Ling et al. designed biodegradation-mediated MoO 3−x NUs with tunable enzyme-mimicking activity, which could selectively exert therapeutic effect via cascaded catalytic reactions in the tumor microenvironment (TME). 39 Meanwhile, normal tissues were not harmed due to the responsive biodegradation of MoO 3−x NUs in the physiological environment (pH ∼7.4) ( Figure 9A). In particular, the MoO 3−x NUs first exhibited CAT-like activity to catalyze the decomposition of H 2 O 2 in TME, generating abundant O 2 for triggering subsequent OXD-like activity. Then, plenty of cytotoxic O 2 •was produced for tumor cell death. This study demonstrated a biodegradation-mediated in vivo catalytic activity-regulated nanozyme for cascaded catalytic therapy of tumor. TME-mediated nanocatalytic strategy of Mo-based nanozyme is promising for improving antitumor effect. Very recently, our group designed a cascaded nanocatalytic reactor (MoS 2 @CGTC NCR) with response to glucose. The NCR loaded GOx and chemotherapeutic drug tirapazamine (TPZ) together on the surface of MoS 2 nanozyme carrier for regulating TME to realize self-enhanced chemocatalytic therapy ( Figure 9B). 124 Based on the ultrahigh intratumoral glucose concentration, the MoS 2 @CGTC NCR could persistently regulate TME through oxidizing glucose to produce gluconic acid and H 2 O 2 , while quickly consuming O 2 to activate chemotherapeutic TPZ. Then, the subordinate POD-like catalytic efficacy of MoS 2 could be remarkably boosted by the self-supplied H + and H 2 O 2 markedly boosted, producing plenty of • OH for nanocatalytic therapy. In the meantime, the MoS 2 nanozyme also depleted GSH to decrease • OH consumption. Hence, this study provides highly promising protocols for combined chemotherapy with cascaded nanocatalytic therapy.
Moreover, RT is still one of the widely used firstline treatment for cancers in clinic. Currently, it is highly desirable to develop efficient nanoradiosensitization system that enhances radiation doses in cancer cells to sensitize RT while sparing normal tissues. Very recently, our group designed a TME-responsive disassembled small-on-large molybdenum disulfide/hafnium dioxide (MoS 2 /HfO 2 ) dextran (M/H-D) nanoradiosensitizer ( Figure 9C). 125 The M/H-D can release the HfO 2 NPs in TME to enhance tumor penetration of the HfO 2 NPs upon NIR exposure, which can solve the bottleneck of insufficient internalization of the HfO 2 NPs. The POD-like catalytic efficiency of M/H-D nanoradiosensitizer could also be increased upon the NIR photothermal exposure, which selectively catalyzed intratumorally overexpressed H 2 O 2 into highly toxic • OH. This TME-responsive precise nanoradiosensitization has achieved improved irradiation effectiveness, potent oxygenation in tumor, and efficient suppression to tumor, which can also be guided by computed tomography and photoacoustic imaging in real time.

Combating bacteria
Bacterial infections are an ever-growing global crisis with devastating consequences to public health care.
Besides the most widely accepted treatment paradigm using antibiotics, nanozymes have been used as powerful antibacterial agents. Recently, 2D materials such as graphene, 126,127 TMDCs, 128 black phosphorus, 129 layered double hydroxides, 130 and transition metal carbides and nitrides (MXenes) 131 have been intensively explored for antimicrobial applications on account of their superior physiochemical properties. 132 For example, the reduction of layers of 2D nanomaterials can enhance their antimicrobial activity. 133 Among these 2D nanomaterials, Mobased TMDCs such as MoS 2 and MoSe 2 can also act as nanozymes to eliminate bacteria. [134][135][136] The underlying antibacterial mechanism of Mo-based nanozymes is to produce ROS to damage bacteria during the mimic enzyme catalytic reaction. Additionally, the few-layered MoS 2 or MoSe 2 can generate a large number of atomically sharp edges, more active sites, larger surface to volume ratio, and higher photothermal therapy efficacy, all of which contribute to oxidative stress and membrane damage to bacteria. Recently, our groups fabricated a biocompatible PEG-MoS 2 NFs with a rough surface as synergistic antibacterial system, which possessed good bacterial trapping capacity, high POD-like catalytic activity, and NIR photothermal conversion efficacy (Figures 10A and 10B). 27   To increase biocompatibility of MoS 2 nanozymes, a positively charged and multiporous MoS 2 -hydrogel for effective antibacterial activity was further proposed by Qu et al. 135 The MoS 2 -hydrogel exhibited POD-like catalytic ability and NIR photothermal property. The PODlike MoS 2 NFs assembled on the hydrogel could pro-duce • OH from the catalytic decomposition of H 2 O 2 to partially kill bacteria, whereas the MoS 2 -hydrogel could capture and confine the bacteria in the region of ROS destruction to strengthen the antimicrobial efficiency (Figure 10C-E). More importantly, by combining the NIR photothermal property and catalytic ability of nanozymes, the nanozyme-hydrogel can achieve a synergistic bactericidal effect. The dermal wound healing rate was accelerated by this strategy. In a further study, Qu et al. also found that MoS 2 NSs can vertically align on copper substrate, simultaneously resulting in a rough surface to capture bacteria and more active defect-rich edge sites to improve POD-like activity. 137 This nanozyme possessed increased antibacterial activity against both E. coli and S. aureus. Very recently, Wang et al. reported a new near-infrared II light-responsive Cu 2 MoS 4 nanozyme with enhanced OXDand POD-like catalytic activities to improve ROS generation for highly efficient killing of bacteria. 138 Although the abovementioned Mo-based nanozymes have been successfully employed to combating bacteria, more effort is required to focus on designing novel Mo-based nanozymes for combating more types of drug-resistance bacteria, promoting long-term wound healing, antibiofilm, and antibiofouling.

Others applications
Despite the abovementioned applications, several studies have also demonstrated Mo-based nanozymes for treatment of Alzheimer's disease (AD). AD is a progressive disorder that causes brain cells to degenerate and die, which is triggered by the accumulation of amyloid beta (Aβ) and oxidative stress. AD therapy can be successfully performed by regulating the catalytic activity of Mo-based nanozymes with antioxidant properties. Recently, Hu's group designed a novel TPP-conjugated 1,2-distearoyl-sn-glycero-3phosphoethanolamine-N-[amino(polyethyleneglycol)-2000]-functionalized MoS 2 (TPP-MoS 2 ) QDs to target the mitochondria in microglia. 139 TPP-MoS 2 QDs with CAT-and SOD-like activities can cross the blood-brain barrier (BBB), then escape from lysosomes, and target mitochondria of the microglia. It has been demonstrated that the TPP-MoS 2 QDs with dual enzyme activity possess the ability to eliminate ROS mainly produced in mitochondria. The neuron protection was accomplished by the synergistic effects of scavenging ROS, downregulating the proinflammatory cytokines IL-1β, IL-6, and TNF-α and upregulating TGF-β. Moreover, the TPP-MoS 2 QDs facilitated microglial polarization from the inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, which was conductive to the protection of neurons. It has been well recognized that proteolysis of Aβ peptides is a promising approach against AD. Accordingly, Qu's group constructed a high-efficiency Aβ-degrading artificial metalloprotease (MoS 2 -Co) using a MoS 2 NSs and a cobalt complex of 1,4,7,10-tetraazacyclodo-decane-1,4,7,10tetraacetic acid (Codota). 140 By binding to the Aβ peptide, MoS 2 -Co can inhibit the formation of β-sheet structures and shorten the distance between cobalt complex and Aβ peptides. Moreover, MoS 2 -Co can generate local heat upon NIR irradiation to destabilize the β-sheet structures of Aβ aggregates. Furthermore, the designed MoS 2 -Co can significantly reduce Aβ-mediated cytotoxicity and cross the BBB. This method may inspire the design of artificial nanozymes for degrading amyloids.

CONCLUSIONS, CHALLENGES, AND FUTURE PERSPECTIVES
Construction of Mo-based nanozymes mimicking the catalytic function of natural enzymes is a challenging task. Elucidation of the relationship between the physicochemical properties and their enzyme-like activities is of great importance in the development and design of Mo-based nanozymes. We have summarized the progress in the development of bioinspired Mo-based nanozymes mainly including POD, OXD, CAT, SOD, and so on. These kinds of Mo-based nanozymes were constructed via various synthesis strategies with physicochemical properties (size, surface modification, morphology, and so on)-related enzyme-like activities and catalytic mechanisms. Especially, the fundamental of its different biomedical applications for biosensing and biodetection, cancer therapy, and combating bacteria is based on the reversible conversion between valence states of Mo(IV)/Mo(V)/Mo(VI), which endows Mo-based nanozymes with both anti-and prooxidative properties. However, a number of critical issues still need to be addressed for further development of Mobased nanozymes.

Challenges in developing new types of Mo-based nanozymes
Further ground-breaking research is required, including improvement in the synthetic techniques to enable highthroughput and affordable synthesis of nanozymes with controlled structures and properties. Moreover, although Mo-based nanozymes have been reported to mimic several enzymes, the research on Mo-based nanozymes mainly focuses on POD-like catalytic activity. Future effort needs to be devoted to exploring new Mo-based nanozymes to mimic other natural enzymes. Thus, the optimal design, controllable preparation, and standardization of Mo-based nanozymes are very important, consequently reducing the learning cycle in nanozyme research and saving development costs. In addition, single-atom nanozymes catalysts can be considered as the limit in the precise design of nanomaterials at the atomic level. Their structural simplicity and homogeneity can facilitate precise identification and characterization of active sites. Thus, design of Mo-based nanozymes with high activity and selectivity by single-atom strategy also represents a novel and promising avenue. 141

Challenges in catalytic activity, mechanisms, and biological effect studies
Mo-based nanozymes can serve as either oxidants or antioxidants in various applications. Generally, some Mobased nanozymes with POD-and OXD-like activities that can produce ROS have been studied as oxidants, whereas others with CAT-and SOD-like activities that can scavenge ROS have been investigated as antioxidants. The impacting factors of the various catalytic activities including external or internal physicochemical properties of Mo-based nanozymes are still required to be further clarified. Moreover, the catalytic specificity and substrate selectivity of Mo-based nanozymes should be considered. Besides adjusting the type of surface modification and the local density of ligands to improve the exposure degree of the active enzyme site, an alternative approach related to the improvement the catalytic activities the introduction of molecular structure of the active site in natural enzymes to nanozymes. In the future, the two most possible forwardlooking ideas for design of Mo-based nanozymes are as follow. (i) The introduction of stimulus-responsive components could provide possibilities for further improving the enzyme-like activity of Mo-based nanozymes. (ii) The synergistic effect of multicomponent such as single atom, dopants, oxides, metals, carbon, polymer, and so on can be used to form Mo-based hybrids to maximize the catalytic efficiency. In addition, collaborative effort from various disciplines, such as computational studies, machine learning, and artificial intelligent techniques, may help to address the deep mechanism study challenge. Furthermore, the molecular imprinting technology may be used to enhance the selectivity of Mo-based nanozymes. 142 More importantly, when administrated into living organisms, the biological fate such as final biodegradation products, pharmacokinetics, and immunogenicity of Mo-based nanozyme systems has not been systematically investigated. Further studies about assessments of cellular role of nanozymes at a relevant dosage, preclinical toxicity under typical conditions, as well as worst case scenarios, with and without appropriate safeguards, are still needed. Especially, understanding the specificity of nano-bio interactions and the corresponding biological responses is of great importance from the perspective of corona and redox reactions in view of the variable oxidation states of the biospired Mo-involved nanozymes.
In conclusion, we believe that systemically administered Mo-based nanozymes still need optimization to be fully accepted in the clinic for disease therapy; however, Mo-based nanozymes that are locally administered as antibacterial will soon find their way to the market.

Challenges in broad catalytic applications
Currently, Mo-based nanozymes have been used for biosensing, cancer therapy, combating bacteria, detection of environmental pollutants, and other antioxidant application. Coupling the characteristics of the tumor microenvironment (such as acidic pH, hypoxia, and tumor stem cells) with the unique properties of Mo-based nanozymes may inspire us to create novel nanozymes for more effective cancer treatment. Taking advantage of their abilities to traverse the BBB and scavenge ROS, Mo-based nanozymes have the potential to be utilized for therapy of brain diseases (stroke and Parkinson's disease). They are also expected to have more other biomedical applications in preclinical and clinical phases such as more effective elimination of biofilms, gene editing, and nanorobots in future. 143,144 We hope that this review will play some imperative role in assisting future developments in biocatalytic field. We and other researchers will continue to explore this promising nanozyme. The unique properties of Mo-based nanozymes and numerous ways in which the properties can be tuned by their variable oxidation states will likely lead to the development of more exciting stand-alone techniques and effective combinations of existing ones.