Fabrication and characterization of asiaticoside-incorporated silk fibroin/hyaluronic acid hydrogel with immunomodulatory properties for diabetic wound management.
Diabetic foot ulcers (DFUs) arise within a dysregulated wound microenvironment in which sustained inflammation, bacterial susceptibility, and excessive oxidative stress collectively impede tissue repair. To address these interrelated barriers, we developed an asiaticoside-loaded silk fibroin/hyaluronic acid composite hydrogel (ASHF) as a bioactive dressing that couples structural support with localized drug delivery. By optimizing the mass ratio of its components, the resulting hydrogel achieved an excellent balance among mechanical compliance, swelling capacity, tissue adhesion, water vapor transmission rate, and enzymatic degradation. In vitro experiments demonstrated that ASHF released asiaticoside in a two-stage manner, was well tolerated by fibroblasts, promoted cell migration, and inhibited Escherichia coli and Staphylococcus aureus. In vivo evaluation in a diabetic mouse model revealed that ASHF-treated wounds closed more rapidly and showed stronger collagen deposition, CD31-positive neovascularization, and re-epithelialization. Dual immunofluorescence staining demonstrated a significant reduction in M1 macrophages (CD68+/CD86+) and a concurrent increase in M2 macrophages (CD68+/CD206+), alongside favorable shifts in local cytokines (decreased IL-6 and increased IL-10). These findings indicate an effective transition of the local immune microenvironment from persistent inflammation toward a pro-reparative state. Transcriptomic analysis of wound tissues further indicated that ASHF intervention was associated with enrichment of glutathione-related metabolic programs and epidermal differentiation signatures, together with upregulation of key genes including Gstm3, Aox4, Hal, and Krt1. These results suggest that ASHF supports diabetic wound repair through coordinated regulation of redox balance, macrophage polarization, and tissue reconstruction, highlighting its potential as a multifunctional dressing for chronic diabetic wounds.