CuPDA@CaO2@Qu: A pH-responsive H2O2-self-supplying nanozyme for stage-programmed therapy of infected wounds

Developing intelligent antibacterial platforms that dynamically modulate therapeutic activities in response to microenvironmental cues is essential to overcome the self-limiting nature and collateral oxidative damage of conventional chemodynamic therapy (CDT). Herein, a multifunctional and self-adaptive nanozyme platform, denoted as CuPDA@CaO 2 @Qu, is developed. It rationally integrates a copper-based metal-organic gel (CuPDA) for pH-dependent enzyme-mimetic switching, calcium peroxide (CaO 2 ) for endogenous hydrogen peroxide (H 2 O 2 ) self-supply, and the natural flavonoid quercetin (Qu) to reinforce anti-inflammatory and antioxidant functions, collectively enabling synergistic and stage-programmed therapy of infected wounds. Specifically, in acidic infected microenvironments, the peroxidase-mimic CuPDA catalyzes CaO 2 -derived H 2 O 2 into highly toxic hydroxyl radical (·OH), effectively disrupting biofilms and eradicating multidrug-resistant (MDR) bacteria, with enhanced efficacy through glutathione depletion. After bacterial clearance, CuPDA self-switches to antioxidant mode, exhibiting superoxide dismutase-glutathione peroxidase mimetic activities that synergize with Qu to scavenge excess reactive oxygen species (ROS), resolve inflammation, and promote M2 macrophage polarization. Moreover, the nanocomposite is capable of promoting cellular migration, collagen deposition, and neovascularization, significantly accelerating tissue healing. This self-adaptive platform demonstrates potent efficacy in MDR bacterial-infected wounds and offers a promising strategy for intelligent nanomedicine design.