Ginsenoside Rg1 Regulates Immune Microenvironment and Neurological Recovery After Spinal Cord Injury Through MYCBP2 Delivery via Neuronal Cell‐Derived Extracellular Vesicles

Abstract Spinal cord injury (SCI) is a severe neurological condition that frequently leads to significant sensory, motor, and autonomic dysfunction. This study sought to delineate the potential mechanistic underpinnings of extracellular vesicles (EVs) derived from ginsenoside Rg1‐pretreated neuronal cells (Rg1‐EVs) in ameliorating SCI. These results demonstrated that treatment with Rg1‐EVs substantially improved motor function in spinal cord‐injured mice. Rg1‐EVs enhance microglial polarization toward the M2 phenotype and repressed oxidative stress, thereby altering immune responses and decreasing inflammatory cytokine secretion. Moreover, Rg1‐EVs substantially diminish reactive oxygen species accumulation and enhanced neural tissue repair by regulating mitochondrial function. Proteomic profiling highlighted a significant enrichment of MYCBP2 in Rg1‐EVs, and functional assays confirmed that MYCBP2 knockdown counteracted the beneficial effects of Rg1‐EVs in vitro and in vivo. Mechanistically, MYCBP2 is implicated in the ubiquitination and degradation of S100A9, thereby promoting microglial M2‐phenotype polarization and reducing oxidative stress. Overall, these findings substantiated the pivotal role of Rg1‐EVs in neuronal protection and functional recovery following SCI through MYCBP2‐mediated ubiquitination of S100A9. This research offers novel mechanistic insights into therapeutic strategies against SCI and supports the clinical potential of Rg1‐EVs.