Self-adaptive nanozymes with enhanced multi-enzyme activities for sequential multimodal therapy of drug-resistant bacteria-infected wounds

Drug-resistant bacterium-infected wounds pose a serious clinical challenge, underscoring the need for therapeutic materials that respond to dynamic healing stages. Herein, we report a sequential multimodal platform embedding a self-adaptive IrPtCu nanozyme into a madecassoside-enriched hyaluronic acid hydrogel (HIPCM) for rapid bacterial eradication and accelerated wound healing. Leveraging trimetallic synergy and pH-adaptive reactive oxygen species (ROS) regulation, IrPtCu nanozyme exhibits strong oxidase, peroxidase, glutathione oxidase, and glutathione peroxidase-like activities, enabling efficient ROS generation and potent antibacterial performance. After disinfection, it switches to ROS scavenging through superoxide dismutase and catalase-like cascades, alleviating oxidative stress and cooperating with madecassoside to promote tissue repair. In a methicillin-resistant Staphylococcus aureus ( MRSA )-infected mouse model, HIPCM demonstrates strong antibacterial efficacy, promotes M2 macrophage polarization and angiogenesis, and accelerates high-quality repair. Preclinical studies in Bama mini-pigs further confirm improved collagen deposition, hair follicle regeneration, and functional restoration. This work offers a comprehensive strategy integrating adaptive nanozymes and natural herbal medicines for treating drug-resistant wounds. Drug-resistant wound treatment requires adaptive response to the microenvironment. Here, authors develop a pH-responsive hydrogel therapy incorporating an IrPtCu nanozyme to sequentially eliminate pathogens and promote tissue regeneration.