Proceedings of the National Academy of Sciences of the United States of AmericaAug 14, 2026

Using special fat-based nanoparticles to cross into the brain for better mRNA treatments

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Updated Aug 15, 2026

Abstract

CA2d lipid nanoparticles effectively delivered mRNA across the blood-brain barrier in multiple animal models.

The blood-brain barrier limits the delivery of mRNA therapeutics to the central nervous system.
CA2d lipid nanoparticles were designed to facilitate mRNA delivery into CNS cells, including neurons and glial cells.
In wild-type mice, Ai14 mice, and nonhuman primates, CA2d LNPs successfully delivered various mRNA cargos.
In a rat model of ischemic stroke, CA2d LNPs that co-delivered thrombolytic and neuroprotective mRNAs reduced infarct volume.
Improved neurological function was observed in rats treated with CA2d LNPs compared to control groups.

Simplified

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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New LNPs crossed the blood-brain barrier in primates and cut stroke damage in rats

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Using special fat-based nanoparticles to cross into the brain for better mRNA treatments

Abstract

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