Self-Amplifying Metal–Covalent Organic Framework for Programmable Antibacterial-Regenerative Therapy via ROS Cascades

Herein, we present an infection microenvironment (IME)-adaptive covalent organic framework (COF), termed Cu–B–COF, engineered through dynamic assembly of a bidentate N -substituted salicylimine-Cu complex [Cu(SALANIH-boronic acid) 2 ] and 5,10,15,20-tetrakis(2,3-dihydroxyphenyl)porphyrin. Cu–B–COF, integrating the characteristics of both metal–organic frameworks (MOFs) and COFs, could be used as a therapeutic agent for infectious wound healing. This intelligent platform features pH/H 2 O 2 -responsive boronate esters, enabling structural reconfiguration, followed by size switching and biodegradability. The Cu-based catalytic centers enable glutathione peroxidase-like (GPx-like) and peroxidase-like (POD-like) activities. Notably, the bidentate salicylimine-Cu units induce a spatial twisted three-dimensional structure, allowing efficient utilization of light energy, promoting both photothermal conversion and photodynamic processes while minimizing losses due to aggregation-induced quenching. As a result, Cu–B–COF exhibits superior photothermal conversion efficiency compared to its porphyrin precursor, while simultaneously demonstrating dual-modal photodynamic capabilities (Type I/II mechanisms), enabling self-adapting therapeutic cascades through three distinct operational phases. The synergistic glutathione (GSH) depletion and photothermal-potentiated POD-mimetic cycling cooperatively amplify hydroxyl radical (•OH) burst and ROS storm generation, enabling deep-tissue pathogen elimination through enhanced catalytic penetration. Subsequent acid neutralization (via H + consumption) and H 2 O 2 scavenging mechanisms concertedly reconstruct a regenerative niche, restoring physiological pH homeostasis while eliminating oxidative stress barriers. Sustained Cu 2+ release drives neoangiogenesis, while antioxidant polyhydroxyl orchestrates matrix reconstruction and epithelial migration. This multiscale engineering strategy overcomes critical limitations of conventional enzyme therapies, including insufficient ROS yield in hypoxic microenvironments, self-limiting catalytic efficiency, and deficient vascular support during tissue remodeling.