Nanotechnological and in vivo characterization of a new generation of brain-permeable nanoparticles for brain-targeted cholesterol delivery in Huntington's disease.

Reduced brain cholesterol synthesis is an early dysfunction that plays a major role in Huntington's disease (HD) pathogenesis. Because the blood-brain barrier (BBB) prevents cholesterol uptake from the circulation, surface-modified, biodegradable, and biocompatible nanoparticles (NPs) that enhance BBB crossing have emerged as promising tools for delivering cholesterol to the brain in HD mouse models. In these models, such NPs have been shown to rescue cognitive, motor, and neuropathological defects. Here, we describe a new formulation of nanoparticles primarily composed of cholesterol and surface-engineered with a short carbon chain fatty acid (BUT) or its variant glucose (Glu) -conjugated (BUT-Glu) to enhance BBB penetration, referred to as BUT-chol-NPs and BUT-Glu-chol-NPs. We characterized key technological and pharmaceutical properties of these NPs and assessed their ability to cross the BBB and reach different brain regions and cell types following systemic administration in wild-type mice. Both BUT-chol-NPs and BUT-Glu-chol-NPs may represent new delivery systems for supplying cholesterol to the HD brain or to treat other neurological disorders in which cholesterol metabolism is impaired.