The paper reports an Angiopep-2–decorated exosome–liposome hybrid that targets LRP-1, exhibits greater stability than exosomes alone, shows LRP-1–dependent uptake and lysosomal evasion in vitro, and crosses the barrier in zebrafish embryos.

This represents a potentially useful BBB-targeting delivery platform for Parkinson's therapeutics, but its direct PD relevance is limited by absence of PD-specific cargo, mechanistic disease models, or mammalian in vivo efficacy data.

Central Nervous System (CNS) diseases, including Parkinson's, Alzheimer's, and brain tumors, are among the most challenging conditions to treat and are associated with high mortality rates. A significant obstacle in conventional treatment methods for CNS diseases is that many drugs struggle to penetrate the blood-brain barrier (BBB), which diminishes their effectiveness. The primary aim of the current study was to develop and characterize a hybrid nanocarrier composed of exosomes and liposomes to facilitate targeted drug delivery across the BBB for future CNS disease therapies. To achieve targeted uptake, we conjugated the exosome-liposome hybrid to the Angiopep-2 peptide (ANG-2), which has a specific affinity for the LRP-1 receptor, found on endothelial cells of the blood-brain barrier. Our results indicate that exosome-liposome hybrid nanoparticles exhibit significantly greater stability than exosomes alone. Moreover, the LRP-1 ligand-decorated exo-lipo hybrids effectively targeted U87 cells (a model cell line that expresses LRP-1) more efficiently than HEK293 (a cell line with low LRP-1 expression). Additionally, our findings demonstrated that these nanocarriers successfully evaded lysosomal degradation in U87 cells. We also assessed the barrier-crossing efficiency of the nanocarriers in vivo using zebrafish embryos.