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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 \u03b2\u2010triketone\u2010based 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\u2010MC3\u2010DMA lipid in siRNA LNPs\u2010mediated 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. 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