Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.

Authors

Siyu Wang, Yichen Zhong, Chang Wang, Meng Tian, Jeffrey L Bennett, Eliza Bliss-Moreau, Yonger Xue, Changyue Yu, Xucheng Hou, Ya Ying Zheng, Haoyuan Li, Zhengwei Liu, Dinglingge Cao, Diana D Kang, Binbin Deng, Yizhou Dong

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 33. Pages e2538147123. Aug 18, 2026. Epub Aug 14, 2026.

Abstract

Messenger RNA (mRNA) therapeutics hold potential for central nervous system (CNS) disease treatment. However, the blood-brain barrier (BBB) presents a major obstacle, preventing efficient delivery of mRNA into the brain. To overcome this challenge, we designed, synthesized, and tested a series of ionizable lipids and formulated them into CNS-accessing lipid nanoparticles (CA LNPs) to deliver mRNA. The lead candidate among them, CA2d LNP, demonstrated efficient mRNA delivery across the BBB following intravenous injection. In wild-type mice, Ai14 mice, and nonhuman primates, CA2d LNPs effectively delivered various mRNA cargos into multiple key CNS cells, including neurons, microglia, and astrocytes, across different brain regions. In an ischemic stroke rat model, CA2d LNPs codelivering thrombolytic agent and neuroprotective mRNAs reduced infarct volume and improved neurological function. Collectively, this CNS-accessing LNP platform provides a promising strategy for overcoming the BBB and enabling effective mRNA-based therapies for a broad range of CNS disorders.

PMID:
42599788
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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