Abstract / Summary
Neuropathic pain (NP) is a chronic disabling disorder with limited effective therapies. Exosomes isolated from the stem cell secretome have emerged as promising candidates because of their anti-inflammatory and neuroregenerative properties. This systematic review evaluated the mechanisms and translational potential of stem cell secretome-derived exosomes for NP. Following PRISMA 2020 guidelines, biomedical databases were searched from inception to Aug 2026. Eligible studies included preclinical and clinical investigations evaluating stem cell secretome-derived exosomes in NP models. Risk of bias was assessed using SYRCLE and RoB 2 or ROBINS-I. Because of substantial heterogeneity, a narrative synthesis was performed. Seventeen studies met the inclusion criteria, including 16 preclinical studies and one pilot clinical study. Most studies investigated mesenchymal stem cell secretome-derived exosomes and demonstrated reductions in pain-related behaviors across chronic constriction injury, diabetic peripheral neuropathy, and chemotherapy-induced peripheral neuropathy models. Therapeutic effects were associated with suppression of neuroinflammatory cytokines, inhibition of microglial activation, enhancement of neurotrophic signaling, and modulation of nuclear factor kappa B (NF-κB) and NOD-like receptor pyrin domain-containing 3 (NLRP3) pathways. The pilot clinical study suggested a favorable safety profile and potential benefit, although human evidence remains insufficient to establish clinical efficacy. Overall methodological quality was moderate, with heterogeneity in stem cell sources, exosome isolation methods, dosing strategies, administration routes, and outcome measures, precluding meta-analysis. Current evidence supports the biological plausibility of stem cell secretome-derived exosomes as emerging candidates for NP; however, randomized clinical trials and standardized vesicle characterization are required to establish efficacy and translational applicability.