RNA interference (RNAi) therapy has great potential for treating inflammatory diseases. However, the development of potent carrier materials for delivering siRNA to macrophages is challenging. Herein, we design a set of ionizable lipid nanoparticles (LNPs) to screen and identify a potent carrier of siRNA for silencing an essential pro-inflammatory cytokine, interleukin-1β (IL-1β) in macrophages. The top performance LNP (114-LNP), containing ionizable lipid with spermine as an amine-head group, facilitated efficient siRNA internalization via multiple endocytosis pathways and achieved effective endosome escape in macrophages. The optimized LNP/siIL-1β achieved strong silencing of IL-1β in both activated Raw 264.7 cells and primary macrophages. Furthermore, systematic administration of 114-LNP/siIL-1β complexes could effectively inhibit IL-1β expression in an acute liver failure model and significantly attenuated hepatic inflammation and liver damage. These results suggest that the optimized ionizable lipid nanoparticle represents a promising platform for anti-inflammation therapies.