Acid-Responsive Bimetallic Peroxide Composite Nanoplatform for Synergistic Therapy of Drug-Resistant Bacterial Infections via Inducing Oxidative Stress and Disrupting Bacterial Energy Metabolism

Bacterial infections, particularly those caused by multidrug-resistant (MDR) bacteria, pose a serious global health threat. The limited efficacy of traditional antibiotic drugs against MDR strains and the slow development of antibiotics necessitate the exploration of alternative therapeutic strategies. Acid-degradable metallic peroxide has emerged as a promising solution, exhibiting broad-spectrum antimicrobial activity with a reduced risk of resistance development. In this study, we have constructed an acid-responsive bimetallic peroxide nanocomposite (ZCS@M@HA) for the treatment of wound infections involving methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). In our design, the copper-doped zinc peroxide (ZC) nanoparticles are prepared and coated with mesoporous silica to obtain core-shell structured ZC@M, which is subsequently loaded with <i>S</i>-nitroso-<i>N</i>-acetylpenicillamine (SNAP) acting as a nitric oxide (NO) donor and capped with sodium hyaluronate (HA) to prevent premature SNAP release. In the acidic microenvironment of infectious sites, ZCS@M@HA releases Zn²⁺, Cu²⁺, and H₂O₂, and the former disrupts bacterial energy metabolism by impairing the electron transport chain. Meanwhile, self-supplied H₂O₂ and Cu²⁺ perform a Fenton-like reaction to generate highly toxic hydroxyl radicals (•OH) for damaging bacterial membranes. Moreover, Cu²⁺ depletes intracellular glutathione (GSH) to augment the oxidative stress. Furthermore, NO released from SNAP triggered by Cu²⁺ and GSH accelerates wound healing by promoting collagen deposition, tissue regeneration, and vascularization. <i>In vivo</i> assays demonstrate the high MRSA inhibition efficacy of ZCS@M@HA with optimal wound healing. The proposed acid-responsive ZCS@M@HA with multi-bactericidal modalities offers an effective approach to fight MDR bacteria and presents a promising strategy for treating wound infections.