Self-Generated NO/ROS Nanoreactor Drives Bacterial Clearance and Angiogenesis in Diabetic Wounds

Diabetic wound healing represents a highly prevalent and economically burdensome complication of diabetes mellitus. The healing is hampered by two pathophysiological barriers: persistent bacterial biofilms and impaired angiogenesis. While reactive oxygen species (ROS)-mediated strategies are promising, their efficacy is limited by exogenous H₂O₂ dependency and rapid oxidant decomposition. In this study, we engineer a multifunctional nanoplatform (SNP/ZnO₂@lipo), which synergizes potent antibacterial ability and angiogenesis capacity. Its architecture features polyvinylpyrrolidone-modified zinc peroxide (ZnO₂) cores with sodium nitroprusside (SNP) adsorbed on their surface, which are further enveloped within cationic phospholipid bilayers. In infected, mildly acidic microenvironments, bacterial phospholipases and membrane instability destabilize the lipid shell, thereby exposing the SNP/ZnO₂ core. The exposed ZnO₂ and SNP then generate H₂O₂, Zn²⁺, Fe²⁺, and NO <i>in situ</i>. The orchestrated ROS and reactive nitrogen species (RNS) cascade achieves synergistic bactericidal efficacy through dual mechanisms: Fe²⁺-mediated Fenton reactions and NO-derived ·NO formation. The continuous <i>in situ</i> production of oxidants overcomes the need for exogenous H₂O₂. <i>In vitro</i>, the platform shows high biocompatibility, a strong antibacterial capacity, and remarkable angiogenic potential. In diabetic murine wound models, SNP/ZnO₂@lipo accelerates wound healing through concurrent clearing of infection and promoting neovascularization. These data identify SNP/ZnO₂@lipo as an intelligent wound microenvironment-responsive nanoplatform that couples microbial eradication with vascular regeneration, offering a promising strategy for treating infected diabetic wounds.