Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntingtonʼs disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood–brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain. SYNOPSIS: (Figure is included in full-text article.)Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntingtonʼs disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function. : Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntingtonʼs disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function.(Figure is included in full-text article.)