Paracyclophane-based ionizable lipids for efficient mRNA delivery in vivo

mRNA therapeutics utilizing lipid nanoparticle (LNP) delivery technology represent a medical innovation for the treatment of various diseases. Amine-derived ionizable cationic lipids have been regarded as the pivotal component of LNPs, which often utilize commercially available small amine molecules as their cores. Given that even minor changes in the structure of ionizable lipids can result in significant differences in the delivery performance, there is a growing need to redesign the lipid amine-cores to optimize mRNA therapy. Here, we rationally design and synthesize a library of 198 paracyclophane-based ionizable lipids (PILs), which are then formulated into LNPs for mRNA delivery in vitro and in vivo. The resulting PIL LNPs displayed favorable characteristics, including appropriate particle sizes, zeta potentials, mRNA binding capability, efficacious endosomal escape, and robust mRNA delivery in vitro. Tailoring the PIL structures further enables mRNA expression specifically in the liver or simultaneously across multi-organs in vivo. Notably, the optimized PIL LNPs demonstrate superior efficacy compared to the U.S. Food and Drug Administration (FDA) approved DLin-MC3-DMA LNPs following intravenous administration. Additionally, when administered intramuscularly, our PIL LNPs exhibit higher efficacy than the SM-102 and ALC-0315 LNPs that are employed in the coronavirus disease 2019 (COVID-19) mRNA vaccines. These findings demonstrate the potential of paracyclophane-based ionizable lipids in advancing mRNA therapeutics, particularly for liver-targeted drugs and vaccines.