Beyond motor recovery: Stem cell‐derived exosomes for sensory restoration and neuropathic pain relief after spinal cord injury
Md Miftahul Mithu, Sahiduzzaman, Shirsendu Narayan Roy, John Jacob Mathew, Devunipalli Karthik Haraveer, Basundhari Thongbam, Kancharllapalli Prasanna Kumar, Sourov Dey, Md ArifuzzamanAbstract
Spinal cord injury (SCI) causes persistent neurological deficits that extend beyond motor impairment, with sensory dysfunction and neuropathic pain substantially compromising quality of life. Stem cell‐derived exosomes have emerged as promising cell‐free therapeutic agents because they deliver diverse bioactive molecules, including proteins, microRNAs, and long non‐coding RNAs, while retaining many of the paracrine benefits of stem cells. This review summarizes recent advances in the application of stem cell‐derived exosomes for sensory restoration and neuropathic pain relief after SCI, with particular emphasis on their underlying mechanisms and emerging delivery strategies. We first discuss exosome biogenesis, molecular composition, intercellular communication, and engineering approaches. We then summarize their established roles in motor recovery through neuroprotection, immunomodulation, axonal regeneration and myelin repair. Importantly, we highlight emerging evidence that stem cell‐derived exosomes may restore sensory function by promoting axonal regeneration, synaptic remodeling, neural differentiation, and glial metabolic reprogramming. In parallel, exosomes alleviate neuropathic pain by suppressing microglial and astrocytic activation, modulating TLR/MyD88/NF‐κB signaling, reducing neuroinflammation and pathological nociceptive signaling, and promoting remyelination and tissue repair. Exosomes also preserve blood‐spinal cord barrier integrity through regulation of endothelial cells, pericytes, matrix metalloproteinases, and vascular signaling, for both motor and sensory recovery. Finally, we discuss challenges related to exosome heterogeneity, manufacturing standardization, delivery, safety, and limited sensory‐specific evidence, and highlight engineering and biomaterial‐based strategies for future clinical translation. Overall, stem cell‐derived exosomes represent a multifunctional therapeutic platform with potential to move SCI treatment beyond motor recovery toward comprehensive sensory restoration and pain management.