Deep Insight of Design,Mechanism,and Cancer Theranostic Strategy of Nanozymes

Since the discovery of enzyme-like activity of Fe3O4 nanoparticles in 2007,nanozymes are becoming the promising substitutes for natural enzymes due to their advantages of high catalytic activity,low cost,mild reaction conditions,good stability,and suitable for large-scale production.Recently,with the cross fusion of nanomedicine and nanocatalysis,nanozyme-based theranostic strategies attract great attention,since the enzymatic reactions can be triggered in the tumor microenvironment to achieve good curative effect with substrate specificity and low side effects.Thus,various nanozymes have been developed and used for tumor therapy.In this review,more than 270 research articles are discussed systematically to present progress in the past five years.First,the discovery and development of nanozymes are summarized.Second,classification and catalytic mechanism of nanozymes are discussed.Third,activity prediction and rational design of nanozymes are focused by highlighting the methods of density functional theory,machine learning,biomimetic and chemical design.Then,synergistic theranostic strategy of nanozymes are introduced.Finally,current challenges and future prospects of nanozymes used for tumor theranostic are outlined,including selectivity,biosafety,repeatability and stability,in-depth catalytic mechanism,predicting and evaluating activities.

A Review on Metal-and Metal Oxide-Based Nanozymes:Properties,Mechanisms,and Applications

Since the ferromagnetic(Fe_(3)O_(4))nanoparticles were firstly reported to exert enzyme-like activity in 2007,extensive research progress in nanozymes has been made with deep investigation of diverse nanozymes and rapid development of related nanotechnologies.As promising alterna-tives for natural enzymes,nanozymes have broadened the way toward clinical medicine,food safety,environmental monitoring,and chemical production.The past decade has witnessed the rapid development of metal-and metal oxide-based nanozymes owing to their remarkable physicochemical proper-ties in parallel with low cost,high stability,and easy storage.It is widely known that the deep study of catalytic activities and mechanism sheds sig-nificant influence on the applications of nanozymes.This review digs into the characteristics and intrinsic properties of metal-and metal oxide-based nanozymes,especially emphasizing their catalytic mechanism and recent applications in biological analysis,relieving inflammation,antibacterial,and cancer therapy.We also conclude the present challenges and provide insights into the future research of nanozymes constituted of metal and metal oxide nanomaterials.

Nanozymes:Versatile Platforms for Cancer Diagnosis and Therapy

Natural enzymes usually suffer from high production cost,ease of denaturation and inactivation,and low yield,making them difficult to be broadly applicable.As an emerging type of artificial enzyme,nanozymes that combine the characteristics of nanomaterials and enzymes are promising alternatives.On the one hand,nanozymes have high enzyme-like catalytic activities to regulate biochemical reactions.On the other hand,nanozymes also inherit the properties of nanomaterials,which can ameliorate the shortcomings of natural enzymes and serve as versatile platforms for diverse applications.In this review,various nanozymes that mimic the catalytic activity of different enzymes are introduced.The achievements of nanozymes in different cancer diagnosis and treatment technologies are summarized by highlighting the advantages of nanozymes in these applications.Finally,future research directions in this rapidly developing field are outlooked.

Gold Nanozymes:From Concept to Biomedical Applications

In recent years,gold nanoparticles have demonstrated excellent enzyme-mimicking activities which resemble those of peroxidase,oxidase,catalase,superoxide dismutase or reductase.This,merged with their ease of synthesis,tunability,biocompatibility and low cost,makes them excellent candidates when compared with biological enzymes for applications in biomedicine or biochemical analyses.Herein,over 200 research papers have been systematically reviewed to present the recent progress on the fundamentals of gold nanozymes and their potential applications.The review reveals that the morphology and surface chemistry of the nanoparticles play an important role in their catalytic properties,as well as external parameters such as pH or temperature.Yet,real applications often require specific biorecognition elements to be immobilized onto the nanozymes,leading to unexpected positive or negative effects on their activity.Thus,rational design of efficient nanozymes remains a challenge of paramount importance.Different implementation paths have already been explored,including the application of peroxidase-like nanozymes for the development of clinical diagnostics or the regulation of oxidative stress within cells via their catalase and superoxide dismutase activities.The review also indicates that it is essential to understand how external parameters may boost or inhibit each of these activities,as more than one of them could coexist.Likewise,further toxicity studies are required to ensure the applicability of gold nanozymes in vivo.Current challenges and future prospects of gold nanozymes are discussed in this review,whose significance can be anticipated in a diverse range of fields beyond biomedicine,such as food safety,environmental analyses or the chemical industry.

Nanozymes in Point-of-Care Diagnosis:An Emerging Futuristic Approach for Biosensing

Nanomaterial-based artificial enzymes(or nanozymes) have attracted great attention in the past few years owing to their capability not only to mimic functionality but also to overcome the inherent drawbacks of the natural enzymes.Numerous advantages of nanozymes such as diverse enzyme-mimicking activities,low cost,high stability,robustness,unique surface chemistry,and ease of surface tunability and biocompatibility have allowed their integration in a wide range of biosensing applications. Several metal,metal oxide,metal–organic framework-based nanozymes have been exploited for the development of biosensing systems,which present the potential for point-of-care analysis. To highlight recent progress in the field,in this review,more than 260 research articles are discussed systematically with suitable recent examples,elucidating the role of nanozymes to reinforce,miniaturize,and improve the performance of point-of-care diagnostics addressing the ASSURED(a ordable,sensitive,specific,user-friendly,rapid and robust,equipment-free and deliverable to the end user) criteria formulated by World Health Organization. The review reveals that many biosensing strategies such as electrochemical,colorimetric,fluorescent,and immunological sensors required to achieve the ASSURED standards can be implemented by using enzyme-mimicking activities of nanomaterials as signal producing components. However,basic system functionality is still lacking. Since the enzyme-mimicking properties of the nanomaterials are dictated by their size,shape,composition,surface charge,surface chemistry as well as external parameters such as pH or temperature,these factors play a crucial role in the design and function of nanozyme-based point-of-care diagnostics. Therefore,it requires a deliberate exertion to integrate various parameters for truly ASSURED solutions to be realized. This review also discusses possible limitations and research gaps to provide readers a brief scenario of the emerging role of nanozymes in state-of-the-art POC diagnosis system development for futuristic biosensing applications.

MXene-Based Composites as Nanozymes in Biomedicine: A Perspective

MXene-based nanozymes have garnered considerable attention because of their potential environmental and biomedical applications.These materials encompass alluring and manageable catalytic performances and physicochemical features,which make them suitable as(bio)sensors with high selectivity/sensitivity and efficiency.MXene-based structures with suitable electrical conductivity,biocompatibility,large surface area,optical/magnetic properties,and thermal/mechanical features can be applied in designing innovative nanozymes with area-dependent electrocatalytic performances.Despite the advances made,there is still a long way to deploy MXene-based nanozymes,especially in medical and healthcare applications;limitations pertaining the peroxidaselike activity and sensitivity/selectivity may restrict further practical applications of pristine MXenes.Thus,developing an efficient surface engineering tactic is still required to fabricate multifunctional MXene-based nanozymes with excellent activity.To obtain MXene-based nanozymes with unique physicochemical features and high stability,some crucial steps such as hybridization and modification ought to be performed.Notably,(nano)toxicological and long-term biosafety analyses along with clinical translation studies still need to be comprehensively addressed.Although very limited reports exist pertaining to the biomedical potentials of MXene-based nanozymes,the future explorations should transition toward the extensive research and detailed analyses to realize additional potentials of these structures in biomedicine with a focus on clinical and industrial aspects.In this perspective,therapeutic,diagnostic,and theranostic applications of MXene-based nanozymes are deliberated with a focus on future per-spectives toward more successful clinical translational studies.The current state-of-the-art biomedical advances in the use of MXene-based nanozymes,as well as their developmental challenges and future prospects are also highlighted.In view of the fascinating properties of MXene-based nanozymes,these materials can open significant new opportunities in the future of bio-and nanomedicine.

A Novel Method Using Flower-like Manganese Oxide Nanozymes for Colorimetric Detection of Ascorbic Acid

This paper proposes a method of utilizing a flower-like MnOx nanozyme to conduct a colorimetric detection of ascorbic acid.The nanozyme is obtained by a chain of reaction of K3[Fe(CN)6],MnSO4·H2O,polyvinyl pyrrolidone(PVP),NH4F,ethanol,and water.During the experimental process,the flower-like nanozyme is added to the mixed solution,including phosphate buffer,H2O2,and 3,3’,5,5’-tetramethylbe nzidine(TMB).The optimum reaction condition as following:pH 3.0,30μL 500mM H2O2,25μL 92 mM TMB,and 30μL 0.1mM nanozyme.Under the optimum condition,the detection range is 2-26mM,and the linear detection range is 2-20mM.

Recent progress in MOFs-based nanozymes for biosensing

Nanozymes are nanomaterials with enzyme-mimicking catalytic activity.Compared to natural enzymes,nanozymes show various properties such as easy to manufacture,stable,adjustable,and inexpensive.Nanozymes play key roles in biosensing,biocatalysis,and disease treatment.As an important kind of nanozymes,metal-organic framework(MOF)-based nanozymes are receiving a lot of attention due to their structural properties and composition.Rationally developing MOF with enzymes-like catalytic properties has opened new perspectives in biosensing.This review summarizes the up-to-date developments in synthesizing two-dimensional and three-dimensional MOF-based nanozymes and their applications in biosensing.Firstly,classification of nanozymes obtained by MOFs is categorized,and different properties of MOF-based nanozymes are described.Then,the distinctive applications of MOF-based nanozymes in identifying various analytes are thoroughly summarized.Finally,the recent challenges and progressive directions in this area are highlighted.

On the Specificity of Nanozymes: A Perspective

We have compiled eight promising strategies for enhancing the specificity and selectivity of nanozymes,as depicted in the comprehensive summary above.Enzymes exhibit intricate and sophisticated structures,including substrate channels and active sites,which can inform the design of nanozymes.Replication of these structural features and the application of facet engineering/doping techniques can significantly enhance the catalytic specificity of nanozymes.Alternatively,the use of Molecularly Imprinted Polymers(MiPs)to coat nanozymes represents an effective approach to impart substrate specificity.Furthermore,several straightforward stopgap strategies have been devised to improve nanozyme specificity for analytical applications,such as the integration of biorecognition elements and nanozyme sensor arrays through surface modification.

The age of vanadium-based nanozymes: Synthesis, catalytic mechanisms, regulation and biomedical applications

Nanomaterials with enzyme-mimic(nanozyme) activity have garnered considerable attention as a potential alternative to natural enzymes, thanks to their low preparation cost, high activity, ease of preservation, and unique physicochemical properties. Vanadium(V) is a transition metal that integrates the benefits of valence-richness, low cost, and non-toxicity, making it a desirable candidate for developing a range of emerging nanozymes. In this review, we provide the first systematic summary of recent research progress on V-based nanozymes. First, we summarize the preparation of V-based nanozymes using both top-down and bottom-up synthesis methods. Next, we review the mechanism of V-based nanozymes that mimic the activity of various enzymes. We then discuss methods for regulating V-based nanozyme activity, including morphology, size, valence engineering, defect engineering, external triggering, and surface engineering. Afterward, we outline various biomedical applications, including therapeutic, anti-inflammatory, antibacterial, and biosensing. Finally, we prospect the challenges and countermeasures for V-based nanozymes based on their development. By summarizing recent research progress on V-based nanozymes, we hope to provide useful insights for researchers to further explore their potential applications and overcome their existing challenges.

Coordinatively unsaturated cobalt single-atom nanozymes for visual pesticides detection by smartphone-based platform

By adjusting the coordination environment of single-atom catalysts,the enzyme-like activity can be finely tuned for highly sensitive biosensing.Herein,we demonstrated that coordinatively unsaturated cobalt-nitrogen sites doped within porous carbon(SA-CoN_(3))could serve as highly efficient oxidase mimic.Compared with the typical planar four-coordination structure(SA-CoN_(4)),the as-obtained single-atom Co nanozymes anchored by three nitrogen atoms are found to display much higher oxidase-like catalytic efficiency.Combined theoretical and experimental analysis revealed that the coordinatively unsaturated Co sites could facilitate adsorption and activation of O_(2) molecule and thus improve their oxidase-like activity.Based on the enhanced oxidase-like activity of SA-CoN_(3),a paper/smartphone sensor for organophosphorus pesticides(OPs)was successfully constructed and used to quantify glyphosate in environmental and food samples with a low detection limit of 0.66μM.This work not only highlights the important role of coordination unsaturation of SA nanozymes for promoting oxidase-like activity,but also provides an easy and cost-effective way to conduct effective quantification of OPs in the field.

Activity regulation and applications of metal-organic framework-based nanozymes

As a new generation of artificial enzymes,nanozymes show outstanding advantages such as high stability,low cost,and facile synthesis,which endow them with promising applications in biomedical and environmental fields.Among the various reported nanozymes,metal-organic frameworks(MOFs)could mimic the active center of natural enzymes and provide a hydrophobic environment,which makes MOFs attractive alternatives to natural enzymes.Owing to the highly structural diversity and tailorability of MOFs,rational design will contribute to improve the activity of MOF-based nanozymes and promote their potential applications in both biomedical and environmental fields.Therefore,a comprehensiye suminary of activity regulatory strategies of MOF-based nanozymes is urgently needed.Firstly,we summarized the activity regulatory strategies of MOFs with intrinsic enzyme-like activities via modulation of metal nodes,ligands,structures and morphologies.Then the applications of MOF-based nanozymes in biosensing,hazardous degradation,antibacterial,and cancer therapy were also introduced.Finally,the current challenges and future perspectives were discussed in depth.It is highly expected that this review will provide a better understanding on the rational design of novel high-performance MOF-based nanozymes.

Glutamate oxidase-integrated biomimetic Fe_(3)O_(4) hybrids as cascade nanozymes for glutamate detection

Herein,a new nanozyme/natural enzyme hybrid biosensor was established for ultrasensitive l-glutamic acid(L-Glu)detection.The Fe_(3)O_(4) nanoparticles with peroxidase-like activity and stability was used as a nanozyme and carrier for immobilizing l-Glutamate oxidase(GLOD)through Schiffff base reaction to construct a chem-enzyme cascade detector.The resultant Fe_(3)O_(4)-GOLD exhibited a wide linear range(10−500μM)and a low detection limit of 6.03μM for L-Glu detection.Furthermore,the Fe_(3)O_(4)-GOLD exhibited excellent pH stability,thermal stability,reusability and storage stability.After repeated nine cycles,Fe_(3)O_(4)-GOLD still retained 70%of its initial activity.Meanwhile,Fe_(3)O_(4)-GOLD maintained 50%of its initial activity after storage for 20 days,while free GLOD only retained 20%of its initial activity.This strategy of integrating biomimetic Fe 3 O4 and natural enzymes for cascade catalysis makes it possible to design an efficient and stable chemo-enzyme composite catalysts,which are promising for applications in biosensing and biomimetic catalysis.

Recent advances in multi-metallic-based nanozymes for enhanced catalytic cancer therapy

Nanozymes have emerged as a promising alternative to natural enzymes,effectively addressing natural enzymes'inherent limitation.Versatility and potential applications of nanozyme span across various fields,with catalytic tumor therapy being one prominent area.This has sparked significant interest and exploration in the utilization of nanozymes for targeted cancer treatment.Recent advancements in interdisciplinary research,nanotechnology,biotechnology,and catalytic technology have led to the emergence of multi-metallicbased nanozymes,which exhibit tremendous potential for further development.This review focuses on investigating the synergistic effects of multimetallicbased nanozymes,aiming to enhance our understanding of their catalytic activities and facilitate their broader applications.We comprehensively survey the remarkable achievements in the synthesis,catalytic mechanisms,and the latest applications of multi-metallic-based nanozymes in cancer catalytic therapy.Furthermore,we identify the current limitations and prospects of multi-metallic-based nanozymes in the development of new materials and the application of novel technologies,along with the potential challenges associated with catalytic cancer therapy.This review underscores the significance of multi-metallic-based nanozymes and emphasizes the need for continued exploration as well as their potential impact on the development of novel materials and the realization of breakthroughs in catalytic tumor therapy.

Single-atom nanozymes:From bench to bedside

Single-atom nanozymes(SANs)are the new emerging catalytic nanomaterials with enzyme-mimetic activities,which have many extraordinary merits,such as low-cost preparation,maximum atom utilization,ideal catalytic activity,and optimized selectivity.With these advantages,SANs have received extensive research attention in the fields of chemistry,energy conversion,and environmental purification.Recently,a growing number of studies have shown the great promise of SANs in biological applications.In this article,we present the most recent developments of SANs in anti-infective treatment,cancer diagnosis and therapy,biosensing,and antioxidative therapy.This text is expected to better guide the readers to understand the current state and future clinical possibilities of SANs in medical applications.

Dual-active-site Fe/Cu single-atom nanozymes with multifunctional specific peroxidase-like properties for S^(2-)detection and dye degradation

Designing single-atom nanozymes with densely exposed metal atom active sites and enhancing catalytic activity to detect pollutants remain a serious challenge.Herein,we reported a single-atom nanozyme with layered stacked Fe/Cu dual active sites(Fe/Cu-NC SAzyme)synthesized via hydrothermal and hightemperature pyrolysis using folic acid as a template.Compared with Fe-NC and Cu-NC SAzyme,Fe/Cu-NC SAzyme has higher peroxidase-like activity,which indicates that the doping of synthesized Fe/Cu bimetals can improve the catalytic activity and that the atomic loading of Fe and Cu in Fe/Cu-NC is 5.5 wt%and 2.27 wt%,respectively.When S^(2-)is added to the Fe/Cu-NC catalytic system,a high-sensitivity and high-selectivity S^(2-)colorimetric sensing platform can be established,with a wide linear range(0.09-6μmol/L)and a low detection limit(30 nmol/L),which can be used to detect S^(2-)in environmental water samples.What’s more,the Fe/Cu-NC SAzyme can activate peroxymonosulfate(PMS)to degrade 99.9%of rhodamine B(Rh B)within 10 min with a degradation kinetics of 0.5943 min^(-1).This work details attractive applications in Fe/Cu-NC SAzyme colorimetric sensing and dye degradation.

New horizons for therapeutic applications of nanozymes in oral infection

As a category of nanomaterials with excellent catalytic efficiency,great substrate specificity,and highrecovery efficiency,nanozymes have attracted increasing attention in various biomedical applications.Currently,numbers of nanozyme-assisted strategies have been well developed for the theranostics ofvarious diseases by taking advantages of their multienzyme-like characteristics,low cost,and highstability.As the most prevalent oral diseases,oral infection poses a global hazard to human health,andcurrent therapeutic options are insufficient to resolve all the clinical issues.Based on their admirableactivity,nanozymes can be frequently employed in the identification and treatment of various oral infectious disorders.Herein,we provide a brief review focused on the classification of nanozymes,analysesof nanozyme-based antibacterial mechanism,research progress in oral bacterial control,and representative studies of nanozyme-assisted oral inflammatory management.Moreover,major challenges andpotential opportunities regarding the use of nanozymes in oral infectious diseases are also highlightedand discussed.This review not only summarizes the recent studies of nanozymes in oral infection butalso promotes the further development of enzyme-mimetic strategies towards various oral diseases.

Gold nanoparticle-decorated MoSe_(2) nanosheets as highly effective peroxidase-like nanozymes for total antioxidant capacity assay

A visual colorimetric detection strategy is reported for total antioxidant capacity(TAC)assay by using 3,3',5,5'-tetramethylbenzidine(TMB)oxidation as chromogenic substrate based on gold nanoparticle-decorated MoSe_(2) nanosheets(Au@MoSe_(2)).Au@MoSe_(2) nanostructures exhibit high peroxidase-like activity and can catalyze H_(2)O_(2)to oxidize TMB.Based on inhibition effect of ascorbic acid(AA)on TMB oxidation,a facile and sensitive colorimetric method was developed for AA detection.Under optimal conditions,the proposed method showed a sensitivity for AA in a concentration range from 2 to 120μM and limit of detection was 0.41μM.Furthermore,the method was employed for TAC assay in actual samples,including commercial beverages and vitamin C tablets.This work represents a model in nanostructure design and will lead to further development of TAC assay in evaluation of antioxidant food quality.

Advances in antioxidative nanozymes for treating ischemic stroke

Ischemic stroke is one of the most common public diseases that increase mortality.In the ischemic brain,blood flow restoration can cause the generation of excess reactive oxygen species(ROS).Endogenous anti-oxidases in the living system,including catalase(CAT)and superoxide dismutase(SOD),can consume the excess ROS by catalysis to regulate inflammation.However,these natural enzymes are difficult to be widely used in the treatment of stroke.Taking advantages of high stability,low cost,and long-term storage,antioxidative nanozymes-mediated treatments have been proven as a promising method against ischemic stroke.To highlight the progress,we summarize the advances in nanozymes with the antioxidative ability for treating ischemic stroke.It is believed that such a promising therapeutic strategy of antioxidative nanozymes will significantly contribute to the field of ischemic stroke.We expect that antioxidative nanozymes will play significant roles in both basic research and clinical applications.

Nanozymes for biomedical applications in orthopaedics

As the next generation of artificial enzymes,nanozymes have attracted increasing attention in biomedical applications due to their multienzyme-like characteristics,multifunctionalities,low cost,and high stability.By taking advantage of their diverse activities,a growing number of nanozyme-mediated therapeutic strategies have been developed for various diseases.Herein,we provide a brief review of the representative studies of nanozymes,especially in orthopaedic diseases over the past decade,which include arthritis,osteoporosis,bone regeneration,bacteria-associated infections,and osteosarcoma.Moreover,the future potential applications and some major challenges are also discussed.This review would not only provide some instructive views of nanozymes but also promote the development of enzyme-mimetic strategies in orthopaedics.