A pH-Adaptive Nanocomposite: A Multi-enzymatic HOF Integrated with CaO ₂ for On-Demand Bacterial Disinfection, Anti-inflammation, and Accelerated Infected Wound Healing

Wound healing is significantly impeded by bacterial infection and excessive inflammation, exacerbated by antibiotic resistance and the accumulation of excessive reactive oxygen species (ROS). To address this challenge, for the first time, we engineered a hydrogen-bonded organic framework (HOF)-based pH-adaptive nanocomposite CaO₂@HOF-Fe by integrating a pH-responsive H₂O₂-generating capability of CaO₂ with multienzymatic activities of a ferriporphyrin-based hydrogen-bonded organic framework (HOF-Fe). In the weakly acidic microenvironment of infected wounds, CaO₂ gradually releases H₂O₂, which is subsequently converted into highly toxic hydroxyl radicals (^•OH) by HOF-Fe with enhanced peroxidase (POD)-like activity, enabling on-demand antimicrobial chemodynamic therapy (CDT); in vitro studies demonstrated that this nanocomposite completely eradicated <i>Staphylococcus aureus</i> and methicillin-resistant <i>S. aureus</i> at a very low concentration of 0.9 and 1.8 μg mL^-1, respectively. Under neutral physiological pH, HOF-Fe exhibits superoxide dismutase (SOD)- and catalase (CAT)-like activities, effectively scavenging excessive ROS and thereby mitigating inflammation. Furthermore, the CAT-like activity of HOF-Fe facilitates oxygen molecular generation from overexpressed H₂O₂, alleviating hypoxia and promoting angiogenesis. By concurrently addressing bacterial burden and excessive inflammation while also facilitating ROS elimination and oxygen generation, the CaO₂@HOF-Fe nanocomposite significantly accelerates the infected wound healing, offering a promising, resistance-mitigating approach for clinical translation in infected wound management.