Abstract 1854: Neurotransmitter-derived lipid nanoparticles (LNPs) for brain-targeted drug delivery

The treatment of central nervous system (CNS) diseases, such as neurodegenerative disorders, brain tumors, brain infections, and stroke, is severely constrained by the blood-brain barrier (BBB) because it prevents the transfer of most of small-molecule drugs and macromolecules (e.g., peptides, gene drugs, and protein drugs) into the brain. We have developed a previously unknown class of neurotransmitter-derived lipidoids (NT-lipidoids) as simple and effective carriers for enhanced brain delivery of several BBB-impermeable cargos. Particularly, doping the NT-lipidoids into BBB-impermeable lipid nanoparticles (LNPs) gave the LNPs the ability to cross the BBB. Using this novel brain delivery platform, we successfully delivered small molecular drug, genes and proteins into the mouse brain via systemic intravenous administration. For example, the BBB-impermeable paclitaxel was delivered to the brain to treat glioma, and genome-editing fusion protein (−27)GFP-Cre recombinase was delivered for effective genome editing in neuronal cells of the Ai14 mouse brain through intravenous injection. Our recent results demonstrate that by doping the NT-lipidoids into BBB-impermeable clinical used liposome nanomedicines can give the nanomedicines the ability to cross the BBB to treat brain tumors and brain infections. We believe this NT-derived LNPs is a new, simple, universal, and effective brain delivery system, which may find wide applications in treating CNS diseases including brain tumors and providing a tool to study the brain function. Citation Format: Shuyu Wang. Neurotransmitter-derived lipid nanoparticles (LNPs) for brain-targeted drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1854.