Design and synthesis of APN and 3CLpro dual-target inhibitors based on STSBPT with anticoronavirus activity.

Coronaviruses (CoVs) have continuously posed a threat to human and animal health. However, existing antiviral drugs are still insufficient in overcoming the challenges caused by multiple strains of CoVs. And methods for developing multi-target drugs are limited in terms of exploring drug targets with similar functions or structures. In this study, four rounds of structural design and modification on salinomycin were performed for novel antiviral compounds. It was based on the strategy of similar topological structure binding properties of protein targets (STSBPT), resulting in the high-efficient synthesis of the optimal compound M1, which could bind to aminopeptidase N and 3C-like protease from hosts and viruses, respectively, and exhibit a broad-spectrum antiviral effect against severe acute respiratory syndrome CoV 2 pseudovirus, porcine epidemic diarrhea virus, transmissible gastroenteritis virus, feline infectious peritonitis virus and mouse hepatitis virus. Furthermore, the drug-binding domains of these proteins were found to be structurally similar based on the STSBPT strategy. The compounds screened and designed based on this region were expected to have broad-spectrum and strong antiviral activities. The STSBPT strategy is expected to be a fundamental tool in accelerating the discovery of multiple targets with similar effects and drugs.

Attitudes toward ophthalmology as a prospective career among pre-clinical medical students in China.

BACKGROUND: A questionnaire was developed and administered to 450 medical students at the Xiangya Medical College, Central South University in Changsha, China to understand the attitudes among medical students in China toward different medical specialties and to find the factors that influenced their choice of career in ophthalmology. PARTICIPANTS: Fourth-year medical students in the five-year program and sixth-year medical students in the eight-year program. METHODS: All the students were asked to rate the importance of nine possible factors in choosing a specialty as their vocation and their first ranked future specialty career choice. RESULTS: When asked about the reasons for choosing to go to medical school, the top four reasons are the ability to help patients, interesting and challenging work, prestige, and job stability. When asked about the reasons for choosing a specialty, the top four reasons are the ability to find employment, financial reward, career upward mobility, and professional pressure. About the first career choice of the future specialty, for clinical medicine students, ophthalmology is the fifth ranked choice for clinical medicine students. 5.6% (five-year) and 3.4% (eight-year) of them choose ophthalmology as their top ranked specialty for their career. For anesthesia medicine and oral medicine students, most of them preferred to choose the same specialty as before. 1.5% (anesthesia) and 4.5% (oral) of them chose ophthalmology as their top ranked specialty. CONCLUSIONS: Medical students in China have numerous factors that motivate their choice in a specialty. Ophthalmology is the fifth ranked choice among clinical medicine students.

Machine Learning Guided Discovery of Superoxide Dismutase Nanozymes for Androgenetic Alopecia.

Androgenetic alopecia (AGA) is a common form of hair loss, which is mainly caused by oxidative stress induced dysregulation of hair follicles (HF). Herein, a highly efficient manganese thiophosphite (MnPS3) based superoxide dismutase (SOD) mimic was discovered using machine learning (ML) tools. Remarkably, the IC50 of MnPS3 is 3.61 µg·mL-1, up to 12-fold lower than most reported SOD-like nanozymes. Moreover, a MnPS3 microneedle patch (MnMNP) was constructed to treat AGA that could diffuse into the deep skin where HFs exist and remove excess reactive oxygen species. Compared with the widely used minoxidil, MnMNP exhibits higher ability on hair regeneration, even at a reduced frequency of application. This study not only provides a general guideline for the accelerated discovery of SOD-like nanozymes by ML techniques, but also shows a great potential as a next generation approach for rational design of nanozymes.

Photo-mediated ultrasound therapy for the treatment of retinal neovascularization in rabbit eyes.

OBJECTIVES: Retinal neovascularization (RNV) is the growth of abnormal microvessels on the retinal surface and into the vitreous, which can lead to severe vision loss. By combining relatively low-intensity ultrasound and nanosecond-pulse-duration laser, we developed a novel treatment method, namely photo-mediated ultrasound therapy (PUT), which holds a potential to remove RNV with minimal or no damage to the adjacent tissues. METHODS: RNV was created in both albino and pigmented rabbits (n = 10) through a single intravitreal injection with DL-α-aminoadipic acid. RNV was treated with PUT 8 weeks postinjection. After PUT treatment, animals were evaluated longitudinally for up to 6 weeks. Treatment outcomes were evaluated through fundus photography, red-free fundus photography, fluorescein angiography (FA), and histopathology. RESULTS: In both albino and pigmented rabbits, there were no leakage in the treatment area immediately after PUT treatment as demonstrated by FA, indicating the cessation of blood perfusion of the RNV in the treated area. The fluorescence leakage did not recover in albino rabbits during the 6-week posttreatment monitoring period, and only 9.9 ± 9.8% of the neovascularization remained at the end of 6 weeks. In the pigmented rabbits, the fluorescence leakage partially returned, but the level of leakage decreased over time during the 6-week posttreatment monitoring period, and only 10.8 ± 9.8% of the neovascularization remained at the end of 6 weeks. Histology demonstrated removal of vasculature without damage to the surrounding neurosensory retina. CONCLUSIONS: These results demonstrate that PUT could precisely remove RNV without damage to the surrounding neurosensory retina in both rabbit strains.

Long-term multimodal imaging characterization of persistent retinal neovascularization using DL-alpha-aminoadipic acid in pigmented and white rabbits.

PURPOSE: Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. METHOD: Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. RESULT: RNV was successfully generated using 50 µL 80 mM DL-AAA solution for DBP rabbits and 80 µL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. CONCLUSION: DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.

A retrospective study to assess the efficacy, safety, and drug survival of secukinumab in plaque psoriasis patients in China.

Secukinumab, a full human immunoglobulin G1κ monoclonal antibody that targets interleukin-17A, has demonstrated remarkable efficacy and appreciable tolerance in patients with moderate-to-severe psoriasis. However, data on its real-life performance, particularly on drug survival in China are limited. To investigate the efficacy, safety, and drug survival of secukinumab in Chinese patients with psoriasis, we conducted a monocentric retrospective study of 66 patients with moderate-to-severe psoriasis to followed-up for 52 weeks. At week 12, 86.4%, 57.6%, and 10.6% of the patients attained 75% improvement in psoriasis area and severity Index (PASI) score from baseline (PASI 75), PASI 90, and PASI 100 responses, respectively. The quality of life of patients markedly improved. The overall survival rate was 74.2%. Adverse events occurred in 30 patients (45.5%). The results revealed favorable efficacy, safety, and tolerability of secukinumab in the treatment of patients with psoriasis and provided data on drug survival in real-life clinical setting in China for the first time.

A new rhodopsin R135W mutation induces endoplasmic reticulum stress and apoptosis in retinal pigment epithelial cells.

Rhodopsin mutations are associated with the autosomal-dominant form of retinitis pigmentosa (RP). Here we report simultaneous occurrence of RP associated with bilateral nanophthalmos and acute angle-closure glaucoma in patient with a new mutation in rhodopsin (R135W). ARPE-19 cells were transfected with myc-tagged wild-type (WT) and R135W rhodopsin constructs. The half-life of WT and R135W rhodopsin was analyzed via cycloheximide chase analysis. We found that R135W rhodopsin was accumulated in the endoplasmic reticulum (ER) and induced unfolded protein response (UPR) and apoptosis. Moreover, chaperone HSP70 alleviated ER stress and prevented apoptosis induced by R135W rhodopsin by attenuating UPR signaling. These findings reveal the novel pathogenic mechanism of RP and suggest that chaperone HSP70 has potential therapeutic significance for RP.

Rhodopsin T17M Mutant Inhibits Complement C3 Secretion in Retinal Pigment Epithelium via ROS Induced Downregulation of TWIST1.

Rhodopsin mutations cause autosomal dominant form of retinitis pigmentosa (RP). T17M rhodopsin predisposes cells to endoplasmic reticulum stress induced apoptosis. However, the pathogenic role of T17M rhodopsin in RP is not completely understood. Complement C3 has a protective role in RP pathogenesis. This study aimed to investigate whether T17M rhodopsin regulates C3 secretion in retinal pigment epithelium. The human retinal pigment epithelial cell line (ARPE-19) was engineered to overexpress wide-type (WT) and T17M rhodopsin. Gene expression was detected by RT-PCR and Western blot analysis. C3 secretion was detected by ELISA. The overexpression of T17M rhodopsin significantly induced ROS and reduced C3 secretion and transcription in ARPE-19 cells, but ROS scavengers could partially rescue reduced C3 secretion and transcription. Mechanistically, we found that ROS suppressed transcription factor TWIST1 which is responsible for activated transcription of C3. In conclusion, our data provide the first evidence that T17M rhodopsin mutant disrupts C3 secretion via the induction of ROS and the suppression of TWIST1. These findings reveal novel insight into the pathogenic role of mutant rhodopsin in RP. J. Cell. Biochem. 118: 4914-4920, 2017. © 2017 Wiley Periodicals, Inc.

A comprehensive review on targeting cluster of differentiation: An attractive strategy for inhibiting viruses through host proteins.

Viral infections continue to pose a significant global public health threat. Targeting host proteins, such as cluster of differentiation (CD) macromolecules, may offer a promising alternative approach to developing antiviral treatments. CDs are cell-surface biological macromolecules mainly expressed on leukocytes that viruses can use to enter cells, thereby evading immune detection and promoting their replication. The manipulation of CDs by viruses may represent an effective and clever means of survival through the prolonged co-evolution of hosts and viruses. Targeting of CDs is anticipated to hinder the invasion of related viruses, modulate the body's immune system, and diminish the incidence of subsequent inflammation. They have become crucial for biomedical diagnosis, and some have been used as valuable tools for resisting viral infections. However, a summary of the structures and functions of CDs involved in viral infection is currently lacking. The development of drugs targeting these biological macromolecules is restricted both in terms of their availability and the number of compounds currently identified. This review provides a comprehensive analysis of the critical role of CD proteins in virus invasion and a list of relevant targeted antiviral agents, which will serve as a valuable reference for future research in this field.

Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies.

Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia. However, it is important to consider the variable efficacy and potential side effects associated with these treatments. There are currently no drugs approved by the Food and Drug Administration for sarcopenia. The ongoing research aims to develop more effective strategies in the future. Our review of research on disease mechanisms and drug development will be a valuable contribution to future research endeavors.

Unveiling the Potential of Nelumbo nucifera-Derived Liensinine to Target The Myostatin Protein and to Counteract Muscle Atrophy.

Muscle atrophy refers to a decline in muscle mass and function, which has become a global concern due to the aging population. Various clinical trials have investigated the inhibitors of myostatin (MSTN). They have shown promising improvements in muscle function and quality of life. However, there are no drugs specifically targeting MSTN that have been approved for clinical use. In this study, we virtually screened liensinine (LIE), a food (Nelumbo nucifera)-derived compound, with low toxicity, from over 1.1 million compounds. We subsequently identified it as a potential candidate that targets MSTN by a cellular thermal shift assay (CETSA) and drug affinity response target stability (DARTS) assay. Further validation through cellular and in vivo studies demonstrated its promising potential in combating muscle atrophy. The mechanism of action may involve hindering the interaction between MSTN and the activin receptor type IIB (ActRIIB) and downregulating the expression of downstream proteins, including the muscle RING-finger protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx)/Atrogin-1, ultimately promoting muscle regeneration. These results provide a strong foundation for future studies to explore the therapeutic potential of LIE in clinical settings.

Anti-Coronavirus Potential of Polyether Ionophores: The New Application of Veterinary Antibiotics in Livestock.

Coronaviruses have consistently posed a major global concern in the field of livestock industry and public health. However, there is currently a lack of efficient drugs with broad-spectrum antiviral activity to address the challenges presented by emerging mutated strains or drug resistance. Additionally, the method for identifying multitarget drugs is also insufficient. Aminopeptidase N (APN) and 3C-like proteinase (3CLpro) represent promising targets for host-directed and virus-directed strategies, respectively, in the development of effective drugs against various coronaviruses. In this study, maduramycin ammonium demonstrated a broad-spectrum antiviral effect by targeting both of the proteins. The binding domains 4 Å from the ligand of both target proteins shared a structural similarity, suggesting that screening and designing drugs based on these domains might exhibit broad-spectrum and highly effective antiviral activity. Furthermore, it was identified that the polyether ionophores' ability to carry zinc ion might be one of the reasons why they were able to target APN and exhibit antiviral effect. The findings of this experiment provide novel perspectives for future drug screening and design, while also offering valuable references for the utilization of polyether ionophores in the management of livestock health.

Rational Design Strategies for Nanozymes.

Nanozymes constitute an emerging class of nanomaterials with enzyme-like characteristics. Over the past 15 years, more than 1200 nanozymes have been developed, and they have demonstrated promising potentials in broad applications. With the diversification and complexity of its applications, traditional empirical and trial-and-error design strategies no longer meet the requirements for efficient nanozyme design. Thanks to the rapid development of computational chemistry and artificial intelligence technologies, first-principles methods and machine-learning algorithms are gradually being adopted as a more efficient and easier means to assist nanozyme design. This review focuses on the potential elementary reaction mechanisms in the rational design of nanozymes, including peroxidase (POD)-, oxidase (OXD)-, catalase (CAT)-, superoxide dismutase (SOD)-, and hydrolase (HYL)-like nanozymes. The activity descriptors are introduced, with the aim of providing further guidelines for nanozyme active material screening. The computing- and data-driven approaches are thoroughly reviewed to give a proposal on how to proceed with the next-generation paradigm rational design. At the end of this review, personal perspectives on the prospects and challenges of the rational design of nanozymes are put forward, hoping to promote the further development of nanozymes toward superior application performance in the future.

Effects of 2-ethylhexyl diphenyl phosphate exposure on the glucolipid metabolism and cardiac developmental toxicity in larval zebrafish based on transcriptomic analysis.

2-Ethylhexyl diphenyl phosphate (EHDPP) is an organophosphorus type of flame retardant. It is mainly used as a flame-retardant plasticizer in the production of flexible polyvinyl chloride. EHDPP is widely present in environment, particularly in aquatic environment. In this study, we reported that EHDPP exposure significantly affected glucose and lipid metabolism in zebrafish larvae, which was reflected by changes in the transcription of relevant genes and decreased levels of glucose, pyruvate, and triglycerides. In addition, the transcriptomic analysis revealed that the differentially expressed genes could enrich various endpoints in zebrafish larvae. Interestingly, EHDPP exposure could not only change the transcription of genes related to glucolipid metabolism but also cause cardiotoxicity by affecting the transcription of genes related to calcium signaling pathways in zebrafish larvae. To support these findings, we confirmed that these genes involved in cardiac morphology and development were significantly upregulated in zebrafish larvae after EHDPP exposure. More importantly, the distance and overlapping area of the atrium and ventricle were also changed in the EHDPP-exposed zebrafish larvae of transgenic Tg (myl7: EGFP). Overall, our study revealed that EHDPP exposure could affect various endpoints related to glucolipid metabolism and cardiac development in the early developmental stages of zebrafish.

Ultrasound-Augmented Multienzyme-like Nanozyme Hydrogel Spray for Promoting Diabetic Wound Healing.

Treatment of diabetic foot ulcers (DFU) needs to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, but the therapeutic efficacy is greatly limited by the diversity and synergy of drug functions as well as the DFU microenvironment itself. Herein, an ultrasound-augmented multienzyme-like nanozyme hydrogel spray was developed using hyaluronic acid encapsulated l-arginine and ultrasmall gold nanoparticles and Cu1.6O nanoparticles coloaded phosphorus doped graphitic carbon nitride nanosheets (ACPCAH). This nanozyme hydrogel spray possesses five types of enzyme-like activities, including superoxide dismutase (SOD)-, catalase (CAT)-, glucose oxidase (GOx)-, peroxidase (POD)-, and nitric oxide synthase (NOS)-like activities. The kinetics and reaction mechanism of the sonodynamic/sonothermal synergistic enhancement of the SOD-CAT-GOx-POD/NOS cascade reaction of ACPCAH are fully investigated. Both in vitro and in vivo tests demonstrate that this nanozyme hydrogel spray can be activated by the DFU microenvironment to reduce inflammation, relieve hypoxia, lower blood glucose, promote angiogenesis, and eliminate pathogenic bacteria, thus accelerating diabetic wound healing effectively. This study highlights a competitive approach based on multienzyme-like nanozymes for the development of all-in-one DFU therapies.

Implications of hydrogen sulfide in colorectal cancer: Mechanistic insights and diagnostic and therapeutic strategies.

Hydrogen sulfide (H2S) is an important signaling molecule in colorectal cancer (CRC). It is produced in the colon by the catalytic synthesis of the colonocytes' enzymatic systems and the release of intestinal microbes, and is oxidatively metabolized in the colonocytes' mitochondria. Both endogenous H2S in colonic epithelial cells and exogenous H2S in intestinal lumen contribute to the onset and progression of CRC. The up-regulation of endogenous synthetases is thought to be the cause of the elevated H2S levels in CRC cells. Different diagnostic probes and combination therapies, as well as tumor treatment approaches through H2S modulation, have been developed in recent years and have become active area of investigation for the diagnosis and treatment of CRC. In this review, we focus on the specific mechanisms of H2S production and oxidative metabolism as well as the function of H2S in the occurrence, progression, diagnosis, and treatment of CRC. We also discuss the present challenges and provide insights into the future research of this burgeoning field.

Rational Design of Orally Administered Cascade Nanozyme for Inflammatory Bowel Disease Therapy.

Inflammatory bowel disease (IBD) affects millions of individuals worldwide annually. Enteric reactive oxygen species (ROS) play critical roles in the physiology and pathology of IBD. Nanozymes hold great promise for the treatment of IBD because of their exceptional ability to regulate redox homeostasis during ROS-related inflammation. However, the rapid development of orally administered, acid-tolerant, antioxidant nanozymes for IBD therapy is challenging. Here, a nine-tier high-throughput screening strategy is established to address the multifaceted IBD treatment demands, including intrinsic stability, radioactivity, solubility, gut microbiome toxicity, biomimetic elements, intermediate frontier molecular orbitals, reaction energy barriers, negative charges, and acid tolerance. Ni3 S4 is selected as the best matching material from 146 323 candidates, which exhibits superoxide dismutase-catalase bienzyme-like activity and is 3.13- and 1.80-fold more active than natural enzymes. As demonstrated in a mouse model, Ni3 S4 is stable in the gastrointestinal tract without toxicity and specifically targets the diseased colon to alleviate oxidative stress. RNA and 16S rRNA sequencing analyses show that Ni3 S4 effectively inhibits the cellular pathways of pro-inflammatory factors and restores the gut microbiota. This study not develops a highly efficient orally administered cascade nanozyme for IBD therapy and offers a next-generation paradigm for the rational design of nanomedicine through data-driven approaches.

Ultrasound activatable microneedles for bilaterally augmented sono-chemodynamic and sonothermal antibacterial therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill bacteria by converting hydrogen peroxide (H2O2) into toxic hydroxyl radical (•OH). Among them, Fenton-type metal peroxide nanoparticles fascinate nanomaterials with intriguing physiochemical properties, but research on this antibacterial agent is still in its infancy. Herein, a distinct CuO2/TiO2 heterostructure constituted of ultrasmall copper peroxide (CuO2) nanoclusters and sonosensitized ultrathin oxygen vacancy-rich porous titanium oxide (OV-TiO2) nanosheets was developed and was incorporated into microneedles for bilaterally augmented sono-chemodynamic and sonothermal antibacterial therapy. Engineering CuO2 nanoclusters on the surface of TiO2 nanosheets not only endows the Fenton catalytic activity for sono-chemodynamic therapy (SCDT), but also improves the sonodynamic and sonothermal performance of TiO2 by narrowing the bandgap of TiO2 and suppressing the recombination of electron-hole pairs. The high efficacy of this CuO2/TiO2 integrated microneedle (CTMN) patch was systematically demonstrated both in vitro and in vivo with the eliminating rate >99.9999% against multidrug resistant (MDR) pathogens in 5 min as well as accelerated wound tissue healing. This work highlights a promisingly new and efficient strategy for the development of sonosensitive and chemoreactive nanomedicine for non-antibiotic therapies. STATEMENT OF SIGNIFICANCE: Feton-type metal peroxides, a novel nanomaterial with self-supplied oxygen and hydrogen peroxide, can achieve effective antimicrobial activity in vitro. However, there is a lack of effective nanomaterial delivery systems and suitable means for in vivo activation/enhancement of antimicrobial activity during bacterial infected skin wound treatment. In this study, we designed and prepared efficient ultrasound activable microneedles that effectively addressed the deficiencies mentioned above and established a new paradigm for efficient utilization of metal peroxide nanomaterials and ultrasound based strategies. Noticeably, copper peroxide nanoclusters/oxygen vacancy-rich porous titanium oxide nanosheets (CuO2/TiO2) integrated microneedle (CTMN) patch combines advantages of both sono-chemodynamic and sonothermal antibacterial therapy, achieving one of the most instant and effective antibacterial efficacy (>99.9999% in 5 min) in vivo reported till now.

Oxidative stress and mitochondrial damage in lambda-cyhalothrin toxicity: A comprehensive review of antioxidant mechanisms.

Lambda-cyhalothrin, also known as cyhalothrin, is an efficient, broad-spectrum, quick-acting pyrethroid insecticide and acaricide and the most powerful pyrethroid insecticide in the world. However, there is increasing evidence that lambda-cyhalothrin is closely related to a variety of toxicity drawbacks (hepatotoxicity, nephrotoxicity, neurotoxicity and reproductive toxicity, among others) in non-target organisms, and oxidative stress seems to be the main mechanism of toxicity. This manuscript reviews the oxidative and mitochondrial damage induced by lambda-cyhalothrin and the signalling pathways involved in this process, indicating that oxidative stress occupies an important position in lambda-cyhalothrin toxicity. The mechanism of antioxidants to alleviate the toxicity of lambda-cyhalothrin is also discussed. In addition, the metabolites of lambda-cyhalothrin and the major metabolic enzymes involved in metabolic reactions are summarized. This review article reveals a key mechanism of lambda-cyhalothrin toxicity-oxidative damage and suggests that the use of antioxidants seems to be an effective method for preventing toxicity.

Piezoelectric Activatable Nanozyme-Based Skin Patch for Rapid Wound Disinfection.

Nanozymes are promising new-generation antibacterial agents owing to their low cost, high stability, broad-spectrum activity, and minimal antimicrobial resistance. However, the inherent low catalytic activity of nanozymes tends to limit their antibacterial efficacy. Herein, a heterostructure of zinc oxide nanorod@graphdiyne nanosheets (ZnO@GDY NR) with unparallel piezocatalytic enzyme mimic activity is reported, which concurrently possesses intrinsic peroxidase-like activity and strong piezoelectric responses and effectively promotes the decomposition of hydrogen peroxide (H2O2) and generation of reactive oxygen species under ultrasound irradiation. Moreover, this piezocatalytic nanozyme exhibits almost 100% antibacterial efficacy against multidrug-resistant pathogens involving methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. In addition, a piezoelectric activatable nanozyme-based skin patch is developed for rapid skin wound disinfections with satisfactory hemocompatibility and cytocompatibility. This work not only sheds light on the development of an innovative piezoelectric activatable nanozyme-based skin patch for rapid wound disinfection but also provides new insights on the engineering of piezocatalytic nanozymes for nanozyme antibacterial therapy.