Blood-brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

Nat Mater. 2025 Feb 17. doi: 10.1038/s41563-024-02114-5.

Chang Wang ^# ¹ ², Yonger Xue ^# ¹ ², Tamara Markovic ^# ³, Haoyuan Li ¹, Siyu Wang ¹, Yichen Zhong ¹ ², Shi Du ¹ ², Yuebao Zhang ², Xucheng Hou ¹ ², Yang Yu ², Zhengwei Liu ¹, Meng Tian ¹, Diana D Kang ¹ ², Leiming Wang ¹, Kaiyuan Guo ¹, Dinglingge Cao ¹, Jingyue Yan ¹ ², Binbin Deng ⁴, David W McComb ⁴ ⁵, Ramon E Parsons ⁶, Angelica M Minier-Toribio ³, Leanne M Holt ³, Jiayi Pan ⁷, Alice Hashemi ⁸, Brian H Kopell ⁸, Alexander W Charney ⁸, Eric J Nestler ⁹, Paul C Peng ¹⁰, Yizhou Dong ¹¹ ¹²

Affiliations

1 Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Biomedical Engineering and Imaging Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
3 Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4 Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA.
5 Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA.
6 Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7 Biogen, Cambridge, MA, USA.
8 Charles Bronfman Institute for Personalized Medicine, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9 Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eric.nestler@mssm.edu.
10 Biogen, Cambridge, MA, USA. paul.peng@biogen.com.
11 Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Biomedical Engineering and Imaging Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu.
12 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. yizhou.dong@mssm.edu.
# Contributed equally.

PMID: 39962245 DOI: 10.1038/s41563-024-02114-5

Abstract

The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood-brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.

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HY-171306

MK16

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Liposome

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