Harmonizing Rigidity and Flexibility: Embedding COF Quantum Dots Into Extracellular Matrix Gel as Carbon Monoxide Depot for Acoustically Triggered Time‐Programmable Anti‐Infective Therapy

ABSTRACT Multidrug‐resistant (MDR) bacterial infections persist as a critical threat due to the dual challenge of pathogen burden and challenging post‐infection tissue repair. Herein, this work presents an acoustically triggered carbon monoxide (CO) depot based on rigid‐flexible integrated polymer networks that are engineered for high‐capacity storage and sustained release of CO for infection‐to‐regeneration. This depot is architected by embedding CO precursor‐loaded metallized covalent organic framework quantum dots (COFQDs) into a decellularized extracellular matrix (ECM) gel network derived from small intestinal submucosa (SIS). The rigid COFQDs with abundant Mn sites enable substantial CO storage after ultrasound, while the flexible ECM acts as a gate that slowly enzymatically degrades for CO release up to 10 days. Upon ultrasound activation, the depot eradicates pathogens via sonodynamic therapy, while the liberated CO suppresses the NF‑κB/MAPK/IRF3 axes to remodel inflammation and synergizes with SIS‑derived growth factors to initiate tissue regeneration. In a murine methicillin‐resistant Staphylococcus aureus (MRSA)‐infected wound model, this depot fulfilled superior scarless healing compared to conventional treatments. This rigid‐flexible synergistic design establishes a compelling paradigm for temporally regulated anti‐infective therapy, offering a promising strategy for managing MDR diseases.