Injectable plant vesicles-biomineralized ZnO2 hydrogel for synergistic chemodynamic antibacterial, anti-inflammatory, and regenerative treatment of infected diabetic wounds.

Chronic diabetic wounds are characterized by persistent bacterial infection, biofilm formation, and dysregulated inflammation, which impair angiogenesis and delay healing. In this work, we developed a multifunctional injectable hydrogel (ZE-OSG) that integrates ZnO2-based chemodynamic therapy (CDT) with the bioactivity of ginger-derived extracellular vesicles (EVs) to eradicate biofilms, resolve inflammation, and promote vascular regeneration. ZnO2-EV nanohybrids were synthesized via biomineralization of ZnO2 directly onto EV, preserving EV bioactivity while enabling localized generation of hydrogen peroxide (H₂O₂) and hydroxyl radicals (·OH). This facilitates potent eradication of methicillin-resistant Staphylococcus aureus (MRSA) and disruption of mature biofilms. After integrating to Schiff base-crosslinked oxidized starch-gelatin hydrogel (OSG), the ZE-OSG hydrogel exhibited injectability, self-healing ability, and prolonged retention at the wound site. In a diabetic mouse model of MRSA-infected wounds, ZE-OSG significantly accelerated wound closure, reduced bacterial burden, suppressed inflammatory cytokines, promoted M1 to M2 macrophage polarization, and enhanced collagen deposition and neovascularization through upregulation of vascular endothelial growth factor (VEGF) and CD31 expression, without systemic toxicity. By integrating the EVs bioactivity with ZnO2-mediated antibacterial CDT within a single injectable hydrogel, ZE-OSG offers a clinically translatable strategy for the comprehensive management of infected chronic wounds.