Peripheral blood is separated from the brain by the presence of central nervous system (CNS) barriers These barriers are essential for brain homeostasis, but are also responsible for the inability of many therapeutic molecules to enter the brain The blood-cerebrospinal fluid (CSF) barrier forms a unique interface between blood and CSF and is composed of a single layer of cuboidal choroid plexus epithelial (CPE) cells that surrounds fenestrated capillaries and loose connective tissue

We hypothesize that targeting the blood-CSF barrier is an attractive strategy to deliver therapeutics to the brain Recently, our group reported that the CPE cells that form the blood-CSF barrier are able to secrete extracellular vesicles (EVs) into the CSF Preliminary experiments revealed that CPE-derived EVs and anti-folate receptor VHHs coated EVs locate to the brain upon intravenous injection

We will perform a detailed biodistribution analysis of CPE-derived and other EVs upon peripheral administration Next, we will identify which proteins are involved in brain targeting and these ligands will be fused with therapeutic VHHs In parallel, the same VHHs will be loaded onto CPE-derived EVs Finally, after determining the biodistribution, therapeutic potential of both the VHH-ligand fusion proteins and the VHH-decorated EVs will be assessed

In conclusion, our study will result in innovative strategies to deliver therapeutic molecules into the brain