AI-Validated Brain Targeted mRNA Lipid Nanoparticles with Neuronal Tropism
Year: 2025
Type: article
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) 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 with our experimental results, providing validation of its predictive capacity. Cell-specific biodistribution analysis in Cre-reporter Ai9 mice showed that acetylcholine-functionalized LNPs preferentially transfected neurons and astrocytes following either intravenous or intracerebral administration. Mechanistic studies suggest that acetylcholine-LNP uptake is mediated by the functional engagement of acetylcholine receptors (AchRs) followed by endocytosis, which synergistically enhances intracellular mRNA delivery. Moreover, acetylcholine-LNPs successfully crossed a human BBB-on-a-chip model, enabling transgene expression in human iPSC-derived neurons. Their effective penetration and transfection in human brain organoids further support their potential activity in human-based systems. These findings establish a predictive and modular framework for engineering CNS-targeted LNPs, advancing precision gene delivery for brain disorders.
DOI: 10.5167/uzh-291113
Authors: Sela, Mor, Chen, Gal, Kadosh, Haim, Kagan, Tomer, Nicola, Raneen, Turutov, Sally, Richtman, Yuval, Zhige, Lin, Albalak Menasherov, Mia R., Kagan, Shaked, Schroeder, Tzur, Mora-Raimundo, Patricia, Kablan, Reaam, Egorov, Egor, Odeh, Anas, Abu-Raiya, Tasneem, Ionita, Inbal, Freilich, Inbar, Kaneti, Galoz, Knani, Ibrahim, Arav, Yehuda, Leichtmann-Bardoogo, Yael, Tadmor, Keshet, Shklover, Jeny, Patriarchi, Tommaso, Danino, Dganit, Hasson, Peleg, Ashery, Uri, Zeisel, Amit, Maoz, Ben M., et al
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7128241104
FWCI:
Cites:
Cited by:
Related to: