IFN ‐ γ ‐Responsive Microglia‐Derived Extracellular Vesicles Impair White Matter Repair After Stroke Through a miR ‐9‐5p/ NEDD4 ‐Dependent Mechanism

ABSTRACT Promoting white matter repair is crucial for functional recovery after ischemic stroke. Our previous study has identified an IFN‐ γ ‐responsive microglia phenotype in the brain after stroke. However, its role in white matter repair remains poorly understood. Herein, we find that extracellular vesicles derived from IFN‐ γ ‐responsive microglia (IFN‐ γ EVs) are internalized by oligodendrocyte precursor cells (OPCs), leading to impaired OPCs proliferation, survival, and differentiation and reduced white matter repair in a murine transient middle cerebral artery occlusion (tMCAO) model. Mechanistically, miR‐9‐5p enrichment in IFN‐ γ EVs suppresses NEDD4 expression, a key regulator of myelination, leading to reduced OPCs maturation and white matter repair. Genetic interventions including miR‐9‐5p knockdown in IFN‐ γ EVs or NEDD4 overexpression in OPCs restore remyelination and functional recovery. Our findings demonstrate that IFN‐ γ EVs act as negative regulators of OPCs differentiation and remyelination following ischemic stroke via miR‐9‐5p/NEDD4 pathway. Targeting this signaling axis may represent a novel therapeutic strategy to enhance remyelination and functional recovery after stroke.