Abstract
OBJECTIVE: Exosomes, as key intercellular communication carriers, can deliver non-coding RNAs (ncRNAs) and proteins to regulate inflammatory networks, but the molecular mechanisms underlying their regulation of macrophage polarization in Spinal cord injury (SCI) remain to be systematically elucidated. This review is to interpret the molecular mechanism of exosomal ncRNA/protein regulating macrophage polarization and inflammatory network in SCI-associated neuroinflammation, and summarize its potential as a therapeutic target. METHODS: We screened PubMed and Embase databases from January 2010 to January 2026 to search for published studies. The search keywords used are as follows: ["exosome cargo" or "exosome"], [ncRNA"], ["spinal cord injury" or "SCI"], ["immune regulation"], ["inflammatory reaction"], ["neuroregeneration" or "nerve"]. 151 peer-reviewed studies on human/animal models were included, and articles that did not meet the requirements were excluded. RESULTS: Exosomes drive SCI pathology via multi-layered molecular networks: Pro-inflammatory exosomal miR-155-5p activates NF-κB/NLRP3 by inhibiting FoxO3a, promoting M1 macrophage polarization and TNF-α/IL-1β/IL-6 release, exacerbating neuronal pyroptosis. Anti-inflammatory exosomal ncRNAs exert synergistic effects: miR-146a targets TLR4/MyD88, miR-340-5p suppresses JAK2/STAT3, and miR-16-5p is sponged by circZFHX3 to upregulate IGF-1, collectively shifting M1→M2 polarization (elevating Arg1/CD206, reducing iNOS/CD16). Exosomal lncGm37494 acts as a ceRNA to sponge miR-130b-3p, upregulating PPARγ. Exosomal proteins (MFG-E8, IL-10) activate SOCS3/STAT3, repairing the blood-spinal cord barrier. Targeted interventions (engineered/MSC-derived exosomes) restore this balance, reducing glial scarring and improving motor function (BBB score elevation). CONCLUSION: Exosomal ncRNA/protein-mediated macrophage polarization and inflammatory pathway regulation are core molecular targets in SCI, offering biosciences-based strategies for precision therapy.