From neural stem cells to cell-free exosome nanotherapy: reprogramming the injured spinal cord microenvironment for regeneration.

Spinal cord injury (SCI) is a severely disabling neurological disorder caused by primary mechanical trauma and subsequent secondary damage, resulting in persistent neurological deficits and imposing a significant social and economic burden. The existing treatment methods - including drug therapy, surgical treatment, and rehabilitation therapy - have limited effects in promoting functional recovery. In recent years, neural stem cells (NSCs) and their derived exosomes have emerged as highly promising innovative treatment options. NSCs promote neural repair through their multifaceted differentiation ability, secretion of neurotrophic factors, and regulation of the immune response in the injured microenvironment. However, factors such as low graft survival rate, ethical restrictions, and the risk of immune rejection have hindered their clinical translation. In contrast, NSC-derived exosomes offer an emerging cell-free alternative solution. NSC-derived exosomes can inhibit neuroinflammation, reduce glial scar formation, enhance axonal regeneration and promote angiogenesis. Compared with the transplantation of NSCs, NSC-derived exosomes may have lower immunogenicity and can avoid direct graft-related excessive proliferation. At the same time, they are convenient for loading, surface modification, and integration with hydrogels, scaffolds, or other nanomaterial delivery systems. Despite these advantages, their clinical application still faces challenges. The main challenges include vesicle heterogeneity, standardization of dosage and efficacy, target specificity of the lesion, biodistribution, timing of treatment, safety of repeated administration, storage stability, and GMP-compliant scalable manufacturing. Overall, NSCs and NSC-derived exosomes demonstrate significant therapeutic potential in the repair of SCI.