Dual‐Enzymatic Nanocatalyst for Optimizing Hypoxia Wound Healing via Linkage‐Enhanced Sonodynamic Antimicrobial Therapy

Abstract Sonodynamic therapy (SDT) has emerged as a promising strategy for addressing multidrug‐resistant bacterial infections by leveraging ultrasound (US)‐activated sensitizers to generate cytotoxic reactive oxygen species (ROS) with high spatiotemporal precision and negligible resistance development. However, clinical translation remains challenging owing to the limited ROS yields in hypoxic infection microenvironments and the scarcity of biocompatible nanosonosensitizers. Inspired by the catalytic architecture of heme‐containing peroxidases, a metalloporphyrin‐based nanozyme, poly (osmium porphyrin) (i.e., Polypor (Os)) is engineered. Upon US irradiation, Polypor (Os) exhibited dual catalytic synergistic effects: 1) sonodynamic production of singlet oxygen ( 1 O 2 ) through energy transfer mechanisms, 2) self‐enhanced ROS amplification via peroxidase‐mimetic (POD) conversion of endogenous H 2 O 2 to hydroxyl radicals, and 3) excellent catalase enzyme (CAT) activity for converting H 2 O 2 into oxygen. The nanoplatform demonstrated local infiltration into infected hypoxic tissues and programmable ROS generation, achieving the complete eradication of facultative anaerobic bacterial methicillin‐resistant Staphylococcus aureus (MRSA) biofilms while preserving mammalian cell viability. Remarkably, mechanistic profiling revealed Polypor (Os)‐mediated activation of the basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) pathways, driving angiogenesis and collagen remodeling in infectious wound models. By integrating dual catalytic nanozyme activities and self‐reinforcing SDT activity, this study establishes a paradigm for precise antimicrobial therapy that concurrently addresses infection control and tissue regeneration through US‐responsive metabolic reprogramming.