RVG-functionalized extracellular vesicles deliver luteolin to brain, suppressing neuroinflammation and restoring cognition

The blood-brain barrier (BBB) represents a major hurdle in central nervous system (CNS) drug development, severely limiting therapeutic access to the brain. Many natural compounds, like the flavonoid luteolin (Lut), possess potent anti-neuroinflammatory properties, but their clinical utility is hampered by poor pharmacokinetics and minimal BBB permeability. Overcoming this delivery challenge is critical for leveraging such compounds against neuroinflammatory diseases and cognitive decline, which currently lack highly effective, brain-targeted treatments.

Researchers engineered a brain-targeting nanoplatform using mesenchymal stem cell-derived extracellular vesicles (MSC-EVs). These EVs were functionalized with a chimeric RVG-CP05 peptide via modular, non-covalent anchoring and then loaded with Luteolin. The resulting RVG@EV-Lut nanocomposite was characterized for 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, comparing RVG@EV-Lut to free Lut and non-targeted vesicles.

RVG-functionalized EVs demonstrated dynamic stability in vitro and significantly increased cellular uptake by both endothelial cells and microglia. This functionalization also enhanced the active transport of Luteolin across the BBB in vitro. In vivo imaging revealed that the RVG@EV-Lut platform achieved superior brain accumulation and prolonged retention compared to free Lut and non-targeted vesicles. This targeted delivery led to a robust suppression of cerebral pro-inflammatory cytokines and reduced neuronal apoptosis. Furthermore, the treatment resulted in the preservation of hippocampal cytoarchitecture.

Critically, these beneficial effects translated into a marked restoration of spatial memory and cognitive performance in the treated mice.