Engineered extracellular vesicles for targeted FGF20 delivery enhance neuroplasticity and functional recovery in ischemic stroke.

Stroke is the second leading cause of death and the primary cause of disability worldwide, yet effective treatments to restore neurological function remain limited. Fibroblast growth factor 20 (FGF20), a promising neurotrophic factor with demonstrated efficacy in neurological disorders, faces a critical translational barrier due to its poor blood-brain barrier (BBB) permeability. To address this limitation, we developed genetically engineered rabies virus glycoprotein (RVG)-modified extracellular vesicles loaded with FGF20 (RVG-FGF20-EVs) for targeted ischemic brain delivery. Systemic administration of RVG-FGF20-EVs in a mouse middle cerebral artery occlusion (MCAO) model significantly reduced infarct volume, enhanced neuroplasticity, and improved long-term functional recovery. Mechanistic investigations revealed that RVG-FGF20-EVs exhibit a distinct miRNA cargo profile, characterized by significant upregulation of miR-181b-5p. Dual-luciferase reporter assays confirmed phosphatase and tensin homolog (PTEN) as a direct target of miR-181b-5p. Our findings demonstrate that RVG-FGF20-EVs promote neuroplasticity and functional recovery post-stroke, mediated at least partially through the miR-181b-5p/PTEN pathway. This study represents the first application of engineered RVG-EVs for efficient FGF20 brain delivery for efficient FGF20 delivery, establishing their unique efficacy in treating ischemic stroke and providing a multifunctional platform for treating neurological disorders. Further optimization and standardization are needed to translate this promising platform into clinical applications. In conclusion, RVG-FGF20-EVs constitute a promising novel therapeutic strategy for ischemic stroke.