Engineered ionizable lipid nanoparticles mediated efficient siRNA delivery to macrophages for anti-inflammatory treatment of acute liver injury

Small interfering RNA (siRNA) mediating specific gene silencing provides a promising strategy for antiinflammatory therapy. However, the development of potent carriers for anti-inflammatory siRNA to macrophages remains challenging. With the aim of realizing potent delivery of siRNA to macrophages, we engineered ionizable lipid nanoparticles (LNPs) with the key component of synthetic lipid-like materials. By varying the amine molecules in the structure of synthetic lipid-like materials, a potent LNP (1O14-LNP) was identified, which exhibited efficient transfection of macrophages by facilitating efficient internalization and endosomal escape. The 1O14-LNP successfully delivered anti-inflammatory siRNA against interleukin-10 (siIL-10) with more than 90% downregulation of IL-10 expression in LPS-activated macrophages. From in vivo studies, systemic administrated 1O14-LNP/siRNA mainly distributed in liver and efficiently captured by hepatic macrophages without notable sign of toxicity. Furthermore, LPS/D-GalN-induced acute liver injury model treated with 1O14-LNP/siIL10 resulted in significant suppression of IL-10 expression and amelioration of liver tissue damage. These results demonstrate that the engineered ionizable LNP provides a powerful tool for siRNA delivery to macrophages and that the strategy of silencing of pro-inflammatory cytokines holds great potential for treating inflammatory diseases.

Automated summary

Small interfering RNA (siRNA) is a promising strategy for specific gene silencing in anti-inflammatory therapy. However, finding efficient carriers for delivering anti-inflammatory siRNA to macrophages remains challenging. In this study, we developed ionizable lipid nanoparticles (LNPs) with synthetic lipid-like materials to deliver siRNA to macrophages. By modifying the structure of synthetic lipid-like materials, we identified a potent LNP (1O14-LNP) that effectively transfects macrophages by promoting internalization and escape from endosomes. 1O14-LNP successfully delivered anti-inflammatory siRNA against interleukin-10 (siIL-10), resulting in significant downregulation of IL-10 expression in LPS-activated macrophages.