From pathophysiology to therapy: molecular mechanisms of stem cell and extracellular vesicle-mediated repair in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent diabetic complication with limited effective treatments. While stem cell-based therapies show promise, their efficacy is attributed to paracrine activity, particularly extracellular vesicles (EVs). This review examines the molecular pathology of DPN, focusing on metabolic dysregulation, neuroinflammation, and neurovascular dysfunction. The mechanisms by which stem cells and their EVs counteract these processes are elucidated, including activating antioxidant pathways (NRF2/HO-1), reprogramming immune signaling (M1 to M2 polarization), and promoting neurovascular regeneration (PI3K/Akt, MAPK). Innovations in EV engineering aimed at enhancing their molecular cargo and targeting specificity are critically assessed. Furthermore, the translational challenges for these EV-based therapies are addressed, focusing on the need for standardized production to ensure molecular consistency. It is concluded that EV-based cell-free therapy represents a novel regenerative strategy for DPN, operating through multi-targeted molecular mechanisms.