Exosomes as emerging mediators and therapeutic vehicles in painful diabetic neuropathy: From pathophysiology to clinical translation

Abstract

Painful diabetic neuropathy (PDN) affects 15%-26% of individuals with diabetes mellitus and remains one of the most common yet therapeutically challenging chronic pain complications. Current first-line treatments, including pregabalin, duloxetine, gabapentin, and tricyclic antidepressants, provide symptomatic relief for only a subset of patients and do not modify the underlying disease process. PDN is driven by chronic hyperglycemia-induced metabolic dysfunction, Schwann cell injury, neuroinflammation, axonal degeneration, and central sensitization. Exosomes, nanosized extracellular vesicles (30-150 nm), have emerged as key mediators of these pathogenic processes by transferring bioactive microRNAs and proteins between Schwann cells, macrophages, endothelial cells, and spinal glia, thereby amplifying nerve injury and pain signaling. In contrast, mesenchymal stem cell-derived exosomes deliver anti-inflammatory and neuroregenerative cargo that improves behavioral, electrophysiological, morphological, and molecular outcomes in preclinical PDN models. Circulating exosomal biomarkers, including miR-21-5p, miR-146a-5p, let-7 family members, neurofilament light chain, and heat shock protein 70, show diagnostic potential but remain limited by insufficient specificity, lack of standardized reference ranges, interlaboratory variability, and the absence of prospective validation. This review critically synthesizes current evidence on the pathogenic, diagnostic, and therapeutic roles of exosomes in PDN, highlights major translational barriers, and emphasizes that exosome-based therapies remain at the preclinical stage with no completed clinical trials in PDN.

Keywords: Exosomes; Extracellular vesicles; Painful diabetic neuropathy; Neuropathic pain; MicroRNA; Mesenchymal stem cells; Neuroinflammation; Biomarkers; Nanoparticle drug delivery; Central sensitization

Core Tip: Exosomes play a central role in painful diabetic neuropathy (PDN) by mediating pathological intercellular signaling while also serving as promising therapeutic vehicles targeting neuroinflammation, axonal degeneration, and pain sensitization. Circulating exosomal microRNA and protein signatures are promising candidate biomarkers, but their clinical application is currently limited by the lack of standardized reference ranges, unresolved specificity across diabetic complications, and confounding effects of diabetic nephropathy, requiring validation in large prospective studies. Likewise, mesenchymal stem cell-derived and engineered exosomes demonstrate robust therapeutic efficacy and neuroprotective effects in preclinical PDN models; however, no clinical trials have yet evaluated these approaches in PDN patients, underscoring the need for clinical translation before they can be considered disease-modifying therapies.