Adipose mesenchymal stem cell-derived exosomes rescue mitochondrial function through SIRT1 to improve diabetic wound healing.

Background: Diabetic wounds represent the most common type of chronic wounds. Persistent inflammation and elevated oxidative stress are hallmark features of chronic wounds, where macrophage phenotypic polarization playing a critical role in the healing process. Adipose-derived mesenchymal stem cell exosomes (ADSC-exos) have shown promising therapeutic effects in the treatment of diabetic wounds by modulating macrophage function. This study aims to elucidate the specific downstream regulatory mechanisms through both Methods: A streptozotocin-induced diabetic mouse model and high glucose-stimulated RAW 264.7 macrophages were utilized to mimic diabetic microenvironments. Wound tissues were collected from patients with diabetic foot ulcer. A skin incision model was established in mice and ADSC-exos were given subcutaneously. Streptozotocin-induced diabetic myeloid-specific Results: In diabetic mice and high glucose-treated macrophages, lysosomal dysfunction preceded mitochondrial and autophagy flux impairments. SIRT1 expression was significantly reduced in both diabetic wound tissues and macrophages, accompanied by M1 macrophage polarization. SIRT1 interference experiments revealed that the impact of ADSC-exos on mitochondrial function, autophagy flux, and inflammatory response were partially dependent on SIRT1. Notably, the therapeutic effects of ADSC-exos on mitochondrial and autophagic pathways were markedly attenuated upon SIRT1 suppression. Conclusions: These findings demonstrate that ADSC-exos promotes diabetic wound healing by restoring mitochondrial function and autophagy via SIRT1 activation. These findings highlight the therapeutic potential of ADSC-exos and provide a mechanistic foundation for future exosome engineering strategies.