Abstract

BACKGROUND The blood-brain barrier (BBB) remains the most formidable obstacle in CNS drug development, severely hindering the delivery of therapeutic agents to the brain. While many natural compounds, such as the flavonoid luteolin (Lut), possess potent anti-neuroinflammatory properties, their clinical potential is restricted by poor pharmacokinetic profiles and minimal BBB permeability. METHODS To address this systemic challenge, we developed a versatile, brain-targeting nanoplatform utilizing mesenchymal stem cell-derived extracellular vesicles (MSC-EVs). For active CNS targeting, these EVs were functionalized with a chimeric RVG-CP05 peptide via modular, non-covalent anchoring and subsequently loaded with Lut. This RVG@EV-Lut nanocomposite was characterized for its physicochemical properties and evaluated using a Transwell-based in vitro BBB model. Therapeutic efficacy and biodistribution were assessed in a C57BL/6J mouse model of LPS-induced neuroinflammation. RESULTS RVG functionalized EV exhibited dynamic stability in vitro, significantly increased cellular uptake by both endothelial cells and microgliaand and enhanced the active transport of Lut across the BBB in vitro. Compared to free Lut and non-targeted vesicles, the RVG@EV-Lut platform demonstrated superior brain accumulation and prolonged retention in vivo imaging. This targeted delivery resulted in a robust suppression of cerebral pro-inflammatory cytokines, reduced neuronal apoptosis, and preservation of hippocampal cytoarchitecture. Critically, these effects were translated into a marked restoration of spatial memory and cognitive performance in the treated mice. CONCLUSION