Furan-Derived Lipid Nanoparticles for Transporting mRNA to the Central Nervous System.

Delivery of mRNA (mRNA) to the central nervous system (CNS) remains a significant challenge. Herein, we design a library of furan-derived lipids and, to our knowledge, for the first time, leverage the meningeal lymphatic vessels (MLVs) route to achieve efficient delivery of mRNA to the brain. These furan-derived lipids were engineered with different furan cores, functional groups, and tails. We found that tetrahydrofuran (THF)-derived lipid nanoparticles (LNPs) generally displayed exceptional mRNA delivery compared to their furan-based counterparts. Specifically, LNPs formulated with four-acetal-tail mono-THF-derived lipid F10T5 and four-acetal-tail di-THF-derived lipid F11T6 demonstrated significantly higher mRNA delivery efficiency to the brain compared with FDA-approved SM102 LNPs. The data revealed that these LNPs bypassed the blood-brain barrier (BBB) via the lymphatic pathway, traveling from deep cervical lymph nodes (dCLNs) to the meninges and subsequently entering brain cells. Collectively, this work provides valuable insights into engineering LNPs and exploring alternative approaches for the delivery of mRNA to the brain.