Preclinical study demonstrates blood-brain barrier penetration and mRNA delivery in rodent and nonhuman primate models, indicating therapeutic utility for central nervous system disorders.
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.
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Wang et al. (2026) studied this question.
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