AI-Validated Brain Targeted mRNA Lipid Nanoparticles with Neuronal Tropism.

ABSTRACT: Targeting therapeutic nanoparticles to the brain poses a challenge due to the restrictive nature of the blood-brain barrier (BBB). Here we report the development of mRNA-loaded lipid nanoparticles (LNPs) functionalized with BBB-interacting small molecules, thereby enhancing brain delivery and gene expression. Screening brain-targeted mRNA-LNPs in central nervous system (CNS) in vitro models and through intravenous administration in mice demonstrated that acetylcholine-conjugated LNPs achieved superior brain tropism and gene expression, outperforming LNP modifications with nicotine, glucose, memantine, cocaine, tryptophan, and other small molecules. An artificial intelligence (AI)-based model designed to predict the BBB permeability of small-molecule ligands showed strong alignment w

SUBMITTER: Sela M 

PROVIDER: S-EPMC12548354 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature