Tanycyte-mediated uptake and transport of PCL nanoparticles in the hypothalamus

Targeted drug delivery to the hypothalamus remains a major challenge due to its intricate structure and the restrictive blood-brain barrier. Tanycytes, specialized glial cells lining the third ventricle, have emerged as potential gatekeepers for mediating substance exchange between cerebrospinal fluid and hypothalamic neurons. Here, we developed PEI-based nanoparticles functionalized with CDCA and LA (PCL) to exploit tanycyte-mediated transport for hypothalamic delivery. Following intracerebroventricular administration in mice, PCL nanoparticles were efficiently internalized by tanycytes and subsequently transported to neurons in the arcuate and ventromedial hypothalamic nuclei, with minimal uptake by astrocytes or microglia. Importantly, PCL administration did not induce neuroinflammation or alter metabolic phenotypes, including body weight, glucose tolerance, and insulin sensitivity. Our findings establish a safe and effective nanoparticle strategy for precise hypothalamic neuronal targeting via tanycyte-dependent pathways, offering a promising platform for treating metabolic and neurological disorders.