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 CaO 2 @HOF–Fe by integrating a pH-responsive H 2 O 2 -generating capability of CaO 2 with multienzymatic activities of a ferriporphyrin-based hydrogen-bonded organic framework (HOF–Fe). In the weakly acidic microenvironment of infected wounds, CaO 2 gradually releases H 2 O 2, 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 Staphylococcus aureus and methicillin-resistant S. aureus 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 H 2 O 2, alleviating hypoxia and promoting angiogenesis. By concurrently addressing bacterial burden and excessive inflammation while also facilitating ROS elimination and oxygen generation, the CaO 2 @HOF–Fe nanocomposite significantly accelerates the infected wound healing, offering a promising, resistance-mitigating approach for clinical translation in infected wound management.