Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

Small interfering RNA (siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases. Nevertheless, the effective delivery of siRNA to desired destination still remains challenging due to poor stability, high molecular weight and negative charge. Currently, ionizable lipid nanoparticle (LNP) has been extensively used as vector for effective delivery of siRNA. Herein, we report a mannose-modified LNP (M-MC3 LNP@TNF alpha) loading tumor necrosis factor alpha (TNF alpha) siRNA for targeting liver macrophages, achieving effectively inhibit acute liver injury. The M-MC3 LNP@TNF alpha not only increases the internalization of LNP by macrophages, but also enhances the gene silencing efficiency of TNF alpha in vitro . Additionally, the M-MC3 LNP@TNF alpha exhibits higher accumulation in liver of healthy mice than that of MC3 LNP@TNF alpha (un-modified LNP) owing to the targeting effect of mannose. As expected, the M-MC3 LNP@TNF alpha significantly suppresses the expression of TNF alpha and ameliorates liver damage in acute liver injury model. Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

Automated summary

A mannose-modified LNP was developed for targeted delivery of TNF alpha siRNA to liver macrophages, achieving effective inhibition of acute liver injury.