Astragaloside IV-loaded exosomes embedded in a GelMA hydrogel enhance angiogenesis and macrophage polarization to accelerate diabetic wound healing.

BACKGROUND

Diabetic wound healing is severely compromised by prolonged inflammation, poor neovascularization, and defective extracellular matrix remodeling. Astragaloside IV (AS-IV), a major bioactive component of Astragalus mongholicus, has shown anti-inflammatory and pro-angiogenic activities that may benefit wound repair. However, its poor water solubility and limited local retention restrict its therapeutic efficacy.

METHODS

Exosomes derived from human umbilical vein endothelial cells (ExoHUVECs) were loaded with AS-IV to generate AS-IV@ExoHUVECs and then embedded in a gelatin methacryloyl (GelMA) hydrogel to form AS-IV@ExoHUVECs@GelMA (AEG). The effects of this formulation on endothelial migration, tube formation, and macrophage polarization were evaluated in vitro. A streptozotocin-induced diabetic wound model was used to assess local retention, wound closure, angiogenesis, inflammation, and tissue remodeling in vivo. Finally, transcriptomic and validation analyses were performed to explore potential molecular mechanisms.

RESULTS

AS-IV@ExoHUVECs promoted endothelial cell migration and tube formation, while driving macrophage polarization toward a pro-repair phenotype under inflammatory conditions. In the diabetic wound model, AEG prolonged local retention and sustained bioactivity at the wound site. Moreover, AEG treatment accelerated wound closure, improved perfusion, enhanced re-epithelialization, and promoted collagen remodeling. These effects were accompanied by increased CD31 and VEGFA expression, reduced CD86, increased CD206, decreased IL-6, and increased IL-10 in wound tissues. RNA-seq identified differences in inflammatory recruitment and cellular stress pathways between AEG- and EG-treated wounds, and subsequent validation showed changes in p53, p21, cleaved caspase-3, and Notch-related markers.

CONCLUSION

Overall, AEG hydrogel promoted diabetic wound healing, at least in part by enhancing angiogenesis and reparative macrophage polarization. This formulation may represent a promising therapeutic strategy for diabetic wounds.