The OCTN2 transporter can be targeted by carnitine functionalised non-ionic surfactant vesicles to deliver drugs across the blood-brain barrier.

Effective treatment of central nervous system diseases is limited by the blood-brain barrier, which restricts the entry of most therapeutics, especially large molecules such as biologics. Here, we demonstrate that coating non-ionic surfactant vesicles with selected ligands markedly enhances their transport across brain endothelium. A focused screen of ligands targeting endothelial receptors and transporters identified glucosamine, transferrin, Angiopep-2, and L-carnitine as promising candidates with enhanced blood-brain barrier transport properties. Mannosamine, which lacks a known endothelial target, served as a non-targeted control. Mechanistic studies indicated dynamin- and clathrin-dependent pathways drove uptake of all functionalised nanoparticles, while caveolae-mediated endocytosis enhanced transport of glucosamine- and L-carnitine-coated vesicles. L-carnitine was of interest because it engages the organic cation transporter OCTN2 that is the primary transporter facilitating carnitine influx at the blood-brain interface; despite reports of its overexpression on brain endothelium, this transporter remains underexplored for targeting drugs. Vesicles coated with L-carnitine enhanced delivery of an antibody across an in vitro barrier model by an order of magnitude compared to free antibody. In a murine Venezuelan equine encephalitis virus infection model, L-carnitine-functionalised vesicles carrying a therapeutic antibody produced substantial reductions in viral burden within both brain and peripheral tissues. These vesicles performed comparably to systems directed at glucose transport pathways and outperformed those targeting transferrin or low-density lipoprotein-related receptors. Overall, the data highlights the flexibility of our vesicle platform for targeted drug delivery and specifically the potential of carnitine functionalisation for effective transport across the blood-brain barrier.