Overcoming the blood–brain barrier using central nervous system–accessing lipid nanoparticles for enhanced mRNA therapeutics
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.
Authors
- Diana D. Kang
- Ya Ying Zheng (ORCID: https://orcid.org/0009-0002-4558-5973)
- Yizhou Dong (ORCID: https://orcid.org/0000-0001-5786-0659)
- Zhengwei Liu (ORCID: https://orcid.org/0009-0003-5105-6709)
- Jeffrey Bennett (ORCID: https://orcid.org/0000-0002-3255-5663)
- Eliza Bliss‐Moreau (ORCID: https://orcid.org/0000-0002-0740-5612)
- Xucheng Hou (ORCID: https://orcid.org/0000-0001-7833-8704)
- Dinglingge Cao (ORCID: https://orcid.org/0009-0007-3776-7474)
- Changyue Yu (ORCID: https://orcid.org/0000-0003-1308-4269)
- Binbin Deng (ORCID: https://orcid.org/0000-0002-4058-0738)
- Meng Tian (ORCID: https://orcid.org/0000-0001-7719-9896)
- Yonger Xue (ORCID: https://orcid.org/0000-0002-6022-2487)
- Chang Wang (ORCID: https://orcid.org/0009-0005-1630-9453)
- Yichen Zhong (ORCID: https://orcid.org/0000-0003-3652-1257)
- Haoyuan Li
- Siyu Wang
Institutions
- Allen Institute for Brain Science (US)
- The Ohio State University (US)
- University of California, Davis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-08-14
- DOI
- https://doi.org/10.1073/pnas.2538147123
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Icahn School of Medicine at Mount Sinai
- National Institute of General Medical Sciences