Neurotrophin-Enriched Extracellular Vesicles Delivery System for Efficient Blood−Brain Barrier Translocation and Neuroprotection

Abstract This study addresses the formidable challenge presented by the blood−brain barrier (BBB) in the treatment of neurological diseases by introducing a biomimetic delivery system utilizing extracellular vesicles, which efficiently crosses the BBB without requiring additional targeting moieties. Inspired by the neurotrophic function of the astrocytes, specifically the release of growth factors like Glial-Derived Neurotrophic Factor (GDNF), we harnessed extracellular vesicles from primary astrocytes (ADE), naturally enriched with GDNF (26.18 ± 4.15 pcg/mL), and subsequently coated them onto mesoporous silica nanoparticles loaded with donepezil (DNP), a model drug to formulate ADE_MSN-DNP. The system proposed BBB permeation and cellular uptake, significantly reduced oxidative stress in a Caenorhabditis elegans model, and increased plasma half-life and brain distribution in C57BL/6 male mice (6−8 months old), as estimated through LC−MS/MS and optical live imaging using Coumarin-6 as a fluorescent probe. The enhanced targeting and efficacy are proposed to be primarily attributed to intact GDNF and the intrinsic homing ability of the extracellular vesicles that facilitate efficient delivery of DNP. These findings provide valuable insights into a neurovascular unit-derived extracellular vesicle system that not only targets the brain and crosses the BBB but also offers a forward-looking strategy for neuroprotection in the mitigation of other neurodegenerative diseases.