High-Yield Extruded Nanovesicles from Adipose Stem Cells Promote High-quality Healing of Diabetic Wound through WNT/beta-Catenin Pathway Activation.

Diabetes is a significant global chronic disease characterized by elevated mortality and disability rates due to persistent infections resulting from refractory wounds. Currently, effective treatment strategies are lacking. Adipose-derived stem cell extracellular vesicles (ADSC-EVs) have been shown to promote skin wound healing; however, their clinical application is impeded by low yield and heterogeneity. We successfully isolated high-yield extruded nanovesicles from adipose stem cells (ADSC-NVs), achieving yields over 30 times greater than those of ADSC-EVs while maintaining similar morphological characteristics. Our findings indicate that ADSC-NVs exhibit a dose-dependent enhancement of proliferation and migration in primary human dermal fibroblasts (HDF) in vitro. Notably, the expression levels of proliferating cell nuclear antigen (PCNA), collagen type I (COL-I), and collagen type III (COL-III) were significantly upregulated in HDF following treatment with ADSC-NVs. RNA-seq analysis further revealed that the differentially expressed genes (DEGs) shared between the ADSC-NVs group and control group were predominantly enriched in the Wnt signaling pathway. Consistently, ADSC-NVs facilitate efficient diabetic wound healing while promoting proliferation and inhibiting inflammation via the Wnt/beta-catenin signaling pathway. In summary, high-yield ADSC-NVs represent a promising alternative to ADSC-EVs for enhancing diabetic wound healing, providing novel insights and methodologies for improving therapeutic outcomes.