Paracyclophane-based ionizable lipids for efficient mRNA delivery in vivo

Area of Science:

• Biotechnology
• Drug Delivery Systems
• Molecular Medicine

Background:

• Messenger RNA (mRNA) therapeutics leverage lipid nanoparticle (LNP) delivery for treating diverse diseases.
• Ionizable cationic lipids are crucial for LNP formulation, with amine cores significantly impacting delivery efficiency.
• Optimizing LNP performance necessitates redesigning lipid amine cores for improved mRNA delivery.

Purpose of the Study:

• To rationally design and synthesize a library of paracyclophane-based ionizable lipids (PILs).
• To evaluate the efficacy of PIL-based LNPs for mRNA delivery in vitro and in vivo.
• To compare the performance of optimized PIL-LNPs against established LNP formulations.

Main Methods:

• Synthesis of 198 paracyclophane-based ionizable lipids (PILs).
• Formulation of PILs into lipid nanoparticles (LNPs) for mRNA delivery.
• In vitro and in vivo assessment of LNP characteristics, mRNA delivery, and therapeutic efficacy.

Main Results:

• PIL-LNPs exhibited optimal particle size, zeta potential, mRNA binding, endosomal escape, and in vitro delivery.
• Tailored PIL structures facilitated targeted mRNA expression in the liver or multi-organ expression in vivo.
• Optimized PIL-LNPs demonstrated superior efficacy compared to FDA-approved DLin-MC3-DMA LNPs and COVID-19 vaccine LNPs (SM-102, ALC-0315).

Conclusions:

• Paracyclophane-based ionizable lipids represent a promising platform for advancing mRNA therapeutics.
• PIL-LNPs offer potential for developing effective liver-targeted mRNA drugs and vaccines.
• This study highlights the significant impact of ionizable lipid structure on mRNA delivery performance.