Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.
S, W., Y, Z., C, W., M, T., JL, B., E, B.M., Y, X., C, Y., X, H., & YY, Z. (2026). Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2538147123
S W, Y Z, C W, M T, JL B, E BM, et al. Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.. Proceedings of the National Academy of Sciences of the United States of America. 2026; doi: 10.1073/pnas.2538147123
S W, Y Z, C W, et al. Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.[J]. Proceedings of the National Academy of Sciences of the United States of America. 2026. DOI: 10.1073/pnas.2538147123.
@article{s2026,
author = {Wang S and Zhong Y and Wang C and Tian M and Bennett JL and Bliss-Moreau E and Xue Y and Yu C and Hou X and Zheng YY},
title = {Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
doi = {10.1073/pnas.2538147123},
note = {PMID: 42599788},
}
TY - JOUR AU - Wang S AU - Zhong Y AU - Wang C AU - Tian M AU - Bennett JL AU - Bliss-Moreau E AU - Xue Y AU - Yu C AU - Hou X AU - Zheng YY TI - Overcoming the blood-brain barrier using central nervous system-accessing lipid nanoparticles for enhanced mRNA therapeutics. T2 - Proceedings of the National Academy of Sciences of the United States of America PY - 2026 DO - 10.1073/pnas.2538147123 AN - PMID:42599788 ER -
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.