Exosomal non-coding RNA cross-talk between DRG neurons and spinal microglia in neuropathic pain: mechanistic insights, neuroimmune reprogramming, and therapeutic opportunities

Neuropathic pain represents a complex chronic pain state arising from nervous system damage or dysfunction, affecting millions worldwide with significant socioeconomic burden. Recent evidence has illuminated a critical role for extracellular vesicle-mediated communication, particularly exosomal transfer of non-coding RNAs (ncRNAs), in the pathogenesis and maintenance of neuropathic pain. This review synthesizes current understanding of exosomal ncRNA cross-talk between dorsal root ganglion (DRG) sensory neurons and spinal cord microglia, focusing on microRNA (miRNA) and circular RNA (circRNA) transfer mechanisms. We examine how DRG-derived exosomes containing specific miRNA cargoes including miR-16-5p, miR-21, miR-23a, and miR-155 modulate microglial activation states, driving the transition from homeostatic surveillance to pro-inflammatory M1 polarization. The molecular mechanisms underlying these communications involve regulation of key signaling pathways including NF- κ B, MAPK, and TLR4-mediated inflammation. Additionally, we explore the emerging roles of circRNAs as stable, abundant regulatory molecules packaged within exosomes that contribute to pain chronification through competing endogenous RNA (ceRNA) networks. Finally, we discuss the therapeutic potential of engineered exosomes for targeted ncRNA delivery to spinal microglia, presenting a paradigm shift toward cell-free, precision therapeutics for neuropathic pain management. This analysis highlights the exosomal ncRNA axis as a promising target for novel pain therapeutics and biomarker development.