Vagus nerve-mediated neuroimmune modulation accelerates remyelination and functional recovery in a preclinical model of multiple sclerosis

Failure of remyelination contributes to persistent disability in multiple sclerosis (MS), yet no approved therapies directly promote central nervous system repair. Observations of enhanced oligodendrocyte maturation signatures during vagus nerve-mediated neuroimmune modulation (VNIM) in the experimental autoimmune encephalomyelitis model of MS prompted us to test whether VNIM could promote remyelination. Here we show that VNIM, delivered as a single 1-minute treatment using clinically relevant parameters, accelerates remyelination and functional recovery in lysolecithin-induced focal demyelination. VNIM reduced lesion volume, increased remyelinated axons with thicker myelin sheaths, enhanced debris clearance, and promoted blood-brain barrier repair. Single-cell transcriptomic analyses revealed that VNIM reshaped the lesion microenvironment by promoting microglial states associated with debris clearance and pro-repair signaling while advancing oligodendrocyte precursor maturation. Together, these findings identify VNIM as a therapeutic strategy that coordinates glial repair programs to accelerate remyelination, providing preclinical rationale for an ongoing clinical trial in relapsing-remitting MS (ClinicalTrials.gov: NCT06796504). This GEO submission includes single-cell RNA sequencing (scRNA-seq) data from lesion, non-lesion, and naïve spinal cord white matter tissue used in this study.