Smart wound healing via a microenvironment-adaptive catalytic platform with multienzyme-like activities

The management of infected chronic wounds remains a formidable challenge due to dynamic shifts in the wound microenvironment and rising antibiotic resistance. An ideal therapeutic strategy should intelligently adapt its function, switching from a potent antibacterial mode in the initial acidic, infected state to an anti-inflammatory and pro-regenerative mode during later healing stages. To address this need, we engineered a pH-gated, smart nanozyme platform, ZIF-8-TA@Cu_s. This system integrates a pH-responsive ZIF-8 core, a tannic acid (TA) functional mediator, and a catalytically engineered Cu₂O/CuO heterojunction surface. In vitro studies confirm that the platform acts as a self-adapting catalytic system: it exhibits dominant peroxidase-like activity under acidic conditions (simulating infection) to generate bactericidal reactive oxygen species (ROS), and switches to potent antioxidant (e.g., superoxide dismutase- and catalase-like) activities under neutral conditions (simulating healing) to scavenge excess ROS. In vivo, in an S. aureus-infected mouse wound model, ZIF-8-TA@Cu_s not only cleared bacteria more effectively than the clinical antibiotic levofloxacin but also actively resolved inflammation by modulating macrophage polarization toward the pro-regenerative M2 phenotype. This intelligent microenvironment-sensing mechanisms autonomously switch functional modes, first eradicating pathogens and then promoting repair, synergistically enhanced angiogenesis, collagen deposition, and tissue regeneration, leading to accelerated, high-quality wound closure finally. This work presents a novel therapeutic paradigm of a feedback-controlled delivery system that dynamically releases context-specific therapeutic actions, moving beyond the controlled release of a single drug to the intelligent programming of multimodal therapeutic functions.