The design and development of novel dressing materials are urgently required for the treatment of chronic wounds caused by diabetic ulcers in clinics. In this study, ursolic acid (UA) extracted from Chinese herbal plants was encapsulated into electrospun nanofibers made from a blend of chitosan (CS) and polyvinyl alcohol (PVA) to generate innovative CS-PVA-UA dressings for diabetic wound treatment. The as-prepared CS-PVA-UA nanofiber mats exhibited randomly aligned fiber morphology with the mean fiber diameters in the range of 100–200 nm, possessing great morphological resemblance to the collagen fibrils which exist in the native skin extracellular matrix (ECM). In addition, the CS-PVA-UA nanofiber mats were found to possess good surface hydrophilicity and wettability, and sustained UA release behavior. The in vitro biological tests showed that the high concentration of UA could lead to slight cytotoxicity. It was also found that the CS-PVA-UA nanofiber dressings could significantly reduce the M1 phenotypic transition of macrophages that was even stimulated by lipopolysaccharide (LPS) and could effectively restore the M2 polarization of macrophages to shorten the inflammatory period. Moreover, the appropriate introduction of UA into CS-PVA nanofibers decreased the release levels of TNF-α and IL-6 inflammatory factors, and suppressed oxidative stress responses by reducing the generation of reactive oxygen species (ROS) as well. The results from mouse hepatic hemorrhage displayed that CS-PVA-UA nanofiber dressing possessed excellent hemostatic performance. The in vivo animal experiments displayed that the CS-PVA-UA nanofiber dressing could improve the closure rate, and also promote the revascularization and re-epithelization, as well as the deposition and remodeling of collagen matrix and the regeneration of hair follicles for diabetic wounds. Specifically, the mean contraction rate of diabetic wounds using CS-PVA-UA nanofiber dressing could reach 99.8% after 18 days of treatment. In summary, our present study offers a promising nanofibrous dressing candidate with multiple biological functions, including anti-inflammation, antioxidation, pro-angiogenesis, and hemostasis functions, for the treatment of hard-to-heal diabetic wounds.

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.