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

An injectable multifunctional hydrogel (ZE-OSG) was made via ginger-derived EV-biomineralized ZnO 2 for chronic wound healing. • ZE-OSG hydrogel showed self-healing, injectability, and prolonged wound-site retention with no toxicity. • ZE-OSG hydrogel showed ZnO 2 -based chemodynamic therapy (CDT) to kill MRSA killing and disrupt biofilm. • ZE-OSG hydrogel preserved the bioactivity of EV to reduce inflammation and promote angiogenesis, thereby accelerating wound healing. 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 ZnO 2 -based chemodynamic therapy (CDT) with the bioactivity of ginger-derived extracellular vesicles (EVs) to eradicate biofilms, resolve inflammation, and promote vascular regeneration. ZnO 2 -EV nanohybrids were synthesized via biomineralization of ZnO 2 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 ZnO 2 -mediated antibacterial CDT within a single injectable hydrogel, ZE-OSG offers a clinically translatable strategy for the comprehensive management of infected chronic wounds.