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

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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