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

Lipid nanoparticles (LNPs) have demonstrated their effectiveness as carriers for the delivery of RNA therapeutics. As the core components of the LNP system, ionizable cationic lipids (ICLs) are still the major focus of research in this field. In this study, we reported a class of novel β-triketone-based ICLs synthesized via click chemistry. We demonstrated that the reaction could be completed instantaneously, and a library of ICLs was generated in a short time. In vitro and in vivo screening identified a lipid that was comparable to FDA approved Dlin-MC3-DMA lipid in siRNA LNPs-mediated gene silencing. In addition, we adopted a computational approach to characterizing the click chemistry in lipid synthesis, as well as the binding between siRNA and ICLs. Our work offers a novel approach to synthesizing ICLs of new structural features, which may not only improve our understanding of the structure-activity relationship (SAR) of ICLs but also lead to the development of improved LNPs for more effective delivery of nucleic acid therapeutics.