Paracyclophane-based ionizable lipids for efficient mRNA delivery in vivo

🥉 Top 5% JournalOct 18, 2024Journal of controlled release : official journal of the Controlled Release Society

New ionizable lipids based on paracyclophane for effective mRNA delivery in living organisms

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A library of 198 paracyclophane-based ionizable lipids demonstrates superior mRNA delivery efficacy compared to FDA-approved lipid nanoparticles.

Optimized paracyclophane-based lipids form lipid nanoparticles (LNPs) that show favorable characteristics for mRNA delivery, including suitable particle sizes and zeta potentials.
These LNPs effectively bind mRNA and facilitate endosomal escape, leading to robust mRNA delivery in vitro.
Tailoring the structures of the lipids allows targeted mRNA expression in the liver or across multiple organs in vivo.
The paracyclophane-based LNPs exhibit greater efficacy than the FDA-approved DLin-MC3-DMA LNPs after intravenous administration.
When delivered intramuscularly, the PIL LNPs outperform SM-102 and ALC-0315 LNPs, which are used in COVID-19 mRNA vaccines.

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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 display 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.

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