Exosome-mediated cell-cell communication: a new perspective on the mechanisms and therapeutic potential of diabetic microvascular complications.

Diabetic microvascular complications, including diabetic kidney disease, diabetic retinopathy, and diabetic peripheral neuropathy, are associated with a growing burden and frequently present as comorbidities, posing substantial therapeutic challenges. Exosomes have been identified as key drivers in the pathogenesis of these conditions by mediating cell-cell communication. This review summarizes the biogenesis, cargo sorting, and uptake of exosomes, with emphasis on how these processes are reprogrammed under metabolic stress, converting exosomes from physiological regulators into carriers of pathological signals. A focused analysis is provided on how metabolic stress reshapes exosomal cargo profiles in each complication, leading to the enrichment of specific microRNAs, proteins, and lipids. These pathological exosomes establish aberrant communication networks among renal, retinal, and neural cells, through which inflammatory responses, oxidative stress, apoptosis, and fibrosis are amplified and vascular injury signals are transmitted, forming self-reinforcing pathological cycles. Exosomes also hold significant promise for clinical translation. Exosomes derived from body fluids carry molecules from injured cells and can serve as non-invasive biomarkers for early diagnosis. Exosome-based therapeutic strategies, particularly those involving stem cell-derived exosomes or exosomes modulated by antidiabetic drugs and natural products, offer multi-target approaches for microvascular intervention. Current challenges include elucidating cross-organ communication networks in comorbid conditions, advancing clinical standardization of exosomal biomarkers, and developing engineered exosomes for precision therapy. An exosome-mediated cell-cell communication perspective provides a more integrated framework for understanding diabetic microvascular comorbidities and may inform the development of multi-complication co-targeting strategies.