Multicomponent thiolactone-based ionizable lipid screening platform for efficient and tunable mRNA delivery to the...

Area of Science:

• Biotechnology
• Drug Delivery
• Molecular Biology

Background:

• Ionizable lipids are crucial for mRNA delivery via lipid nanoparticles (LNPs).
• Designing effective ionizable lipids with improved protein expression, endosomal escape, and organ targeting remains a significant challenge due to complex structure-activity relationships.

Purpose of the Study:

• To develop a high-throughput platform for screening novel ionizable lipids.
• To identify superior ionizable lipids for enhanced mRNA delivery and targeted organ delivery.
• To investigate structure-activity relationships for optimizing LNP formulations.

Main Methods:

• A scalable, one-pot, two-step reaction was employed for synthesizing and screening 91 new ionizable lipids.
• In vivo screening and structure-activity relationship studies were conducted.
• A one-step strategy was used to synthesize a permanently cationic lipid for targeted delivery studies.

Main Results:

• The novel lipid CP-LC-0729 demonstrated significantly higher protein expression compared to the MC3 benchmark, with preliminary studies indicating no in vivo toxicity.
• A permanently cationic lipid formulation achieved highly selective lung delivery, increasing in vivo protein expression 32-fold and outperforming current endogenous targeting strategies.

Conclusions:

• The developed lipid platform accelerates the discovery of advanced ionizable lipids for mRNA delivery.
• CP-LC-0729 represents a promising candidate for improving mRNA delivery efficiency and specificity.
• The findings highlight the potential for targeted organ delivery and enhanced therapeutic outcomes using novel lipid formulations.