Identification of a potent ionizable lipid for efficient macrophage transfection and systemic anti-interleukin-1β siRNA delivery against acute liver failure

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-1 beta (IL-1 beta) 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-1 beta achieved strong silencing of IL-1 beta in both activated Raw 264.7 cells and primary macrophages. Furthermore, systematic administration of 114-LNP/siIL-1 beta complexes could effectively inhibit IL-1 beta 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.

Automated summary

RNA interference therapy shows great potential in treating inflammatory diseases, but developing potent carrier materials for delivering siRNA to macrophages is challenging. This study designed ionizable lipid nanoparticles to carry siRNA for silencing IL-1 beta in macrophages, achieving efficient internalization and endosome escape. The optimized LNP/siIL-1 beta successfully silenced IL-1 beta in both activated cells and primary macrophages, indicating its potential for anti-inflammation therapies.