Targeting nanoparticles to the brain by exploiting the blood–brain barrier impermeability to selectively label the brain endothelium
This approach revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies.
Abstract
<jats:title>Significance</jats:title><jats:p>Therapy-loaded nanoparticles may be directed to the brain by functionalization with ligands targeting blood–brain barrier (BBB)-associated proteins. However, such targeting strategies have inherent brain-specificity limitations, as the target proteins are also significantly expressed in peripheral organs. Here, we present a counterintuitive targeting strategy that exploits the high impermeability of the BBB to selectively retain ligand labels on the surface of brain endothelium. Nanoparticles capable of binding the displayed ligands are consequently directed specifically to the brain microvasculature. This two-step targeting strategy paves the way to overcome the peripheral “off-target” nanoparticle accumulation, increasing the clinical translation of nanoparticle-based therapies. In addition, it shifts the identification of brain-target proteins from focusing on differential expression to instead focus on differential endocytic rates.</jats:p>