β-Triketone-Based Ionizable Cationic Lipids Synthesized via Click Chemistry for siRNA Delivery

Area of Science:

• Biochemistry
• Materials Science
• Drug Delivery

Background:

• Lipid nanoparticles (LNPs) are effective carriers for RNA therapeutics.
• Ionizable cationic lipids (ICLs) are crucial components of LNPs, driving research in this area.
• Developing novel ICLs is key to enhancing nucleic acid therapeutic delivery.

Purpose of the Study:

• To synthesize and characterize a novel class of beta-triketone-based ICLs using click chemistry.
• To evaluate the performance of these novel ICLs in LNP formulations for gene silencing.
• To computationally analyze the click chemistry synthesis and siRNA-ICL binding.

Main Methods:

• Synthesis of beta-triketone-based ICLs utilizing click chemistry.
• In vitro and in vivo screening of synthesized ICLs for gene silencing efficacy.
• Computational modeling to characterize click chemistry and siRNA-ICL interactions.

Main Results:

• Instantaneous click chemistry enabled rapid generation of a diverse ICL library.
• One novel ICL demonstrated gene silencing efficacy comparable to FDA-approved Dlin-MC3-DMA.
• Computational analysis provided insights into synthesis and binding characteristics.

Conclusions:

• A novel, efficient click chemistry approach for synthesizing beta-triketone-based ICLs was established.
• The identified ICL shows promise for developing advanced LNPs for nucleic acid therapeutics.
• This work enhances understanding of ICL structure-activity relationships for improved LNP design.