Multifunctional Hydrogel Dressing Loaded with DH-EVs Promotes Healing of Bacteria-Infected Diabetic Wounds

Abstract

Background: Persistent inflammation and excessive neutrophil extracellular trap (NET) formation hinder the healing of bacteria-infected diabetic wounds. The Salvia miltiorrhiza–Astragalus membranaceus herb pair possesses anti-inflammatory activity, but its poor solubility, rapid metabolic clearance, and unclear material basis limit direct wound application. Extracellular vesicles (DH-EVs) isolated from this herb pair may improve local delivery and stability. Therefore, this work constructs a DH-EV-incorporated hydrogel dressing aimed at inhibiting NET formation and facilitating diabetic wound healing. Methods: DH-EVs were isolated from the Salvia miltiorrhiza–Astragalus membranaceus pair, characterized by lipidomics and small-RNA sequencing, and incorporated into a hydrogel. The dressing was evaluated for physicochemical properties, mechanical performance, biocompatibility, NET inhibition, anti-inflammatory activity, and therapeutic efficacy in vitro and in bacteria-infected diabetic wounds. Results: DH-EVs were isolated, and sequencing identified miRNAs potentially regulating inflammation- and NET-related pathways. Incorporation into hydrogel did not significantly alter mechanical integrity or biocompatibility. In vitro and in vivo, the DH-EV-loaded hydrogel suppressed excessive NET formation, reduced local inflammation, and improved wound closure and tissue regeneration in bacteria-infected diabetic wounds. Conclusions: The DH-EV-loaded hydrogel promotes bacteria-infected diabetic wound repair by suppressing excessive NET formation and inflammation, providing a promising strategy for localized wound treatment.