Adipose-derived stem cell extracellular vesicles in diabetic microangiopathy: from pathological networks to clinical translation

Diabetic microangiopathy (DMA) is a major cause of morbidity and mortality in diabetes. Its pathogenesis involves interconnected processes, including metabolic disturbance, oxidative stress, inflammation, immune dysregulation, endothelial dysfunction, mitochondrial abnormalities, and impaired tissue repair. This complexity suggests that therapeutic strategies targeting individual pathways may be insufficient to address the multidimensional pathological processes underlying DMA. Adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) have emerged as potential cell-free therapeutic candidates whose multimolecular cargo may modulate multiple disease-relevant processes. Preclinical evidence suggests that ADSC-EVs can influence oxidative stress, inflammation, angiogenesis, immune responses, and tissue repair, providing a potential basis for multitarget modulation of pathological microenvironments. This review critically evaluates organ-specific evidence for ADSC-EVs in diabetic retinopathy, diabetic kidney disease, diabetic peripheral neuropathy, and diabetic chronic wounds, with particular attention to evidence specificity, therapeutic mechanisms, delivery barriers, and translational limitations. We further summarize advances in EV engineering, including parent-cell and cargo engineering, surface modification, biomaterial integration, and stimuli-responsive delivery, while distinguishing ADSC-EV-specific findings from evidence extrapolated from the broader EV field. Finally, we discuss major barriers to clinical translation, including manufacturing standardization, potency assessment, biodistribution, organ-specific delivery, long-term safety, and regulatory evaluation. Future studies integrating disease stratification, multi-omics, rational engineering, and standardized manufacturing may help determine whether the multitarget effects of ADSC-EVs can be translated into reproducible and clinically meaningful therapies for DMA.