Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis

• Published in: Journal of controlled release Vol. 343; pp. 175 - 186
• Main Authors: Zhou, Jing-E, Sun, Lei, Liu, Li, Jia, Yujie, Han, Yuqiao, Shao, Jiaqi, Wang, Jing, Wang, Yiting, Yu, Lei, Yan, Zhiqiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2022
• Subjects: Animals; Disease Models, Animal; docosahexaenoic acid; fatty liver; genes; HMGB1 Protein - metabolism; HMGB1 siRNA; inflammation; Inflammation - pathology; Liposomes; liver; Liver - metabolism; liver cirrhosis; Liver Cirrhosis - metabolism; liver function; Macrophages; Macrophages - metabolism; mannose; Mannose receptor; Mice; Mice, Inbred C57BL; Nanoparticles; NASH; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; nucleoproteins; phenotype; protein synthesis; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - therapeutic use; Stable nucleic acid lipid nanoparticles; therapeutics; Mannose receptor; Stable nucleic acid lipid nanoparticles; HMGB1 siRNA; NASH; Macrophages
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2022.01.038

HMGB1 is an inflammatory factor produced by macrophages after liver injury, which plays a key role in promoting NASH progression and further developing into liver fibrosis and cirrhosis. In this study, a mannose-modified HMGB1-siRNA loaded stable nucleic acid lipid particle delivery system (mLNP-siHMGB1) was constructed to target liver macrophages with mannose receptor mediation, thereby silencing HMGB1 protein expression and treating NASH. We also examined the effect of co-administration with docosahexaenoic acid (DHA), a kind of unsaturated fatty acid, on NASH. The results showed that mLNP-siHMGB1 could target macrophages through mannose receptors, effectively silence HMGB1 gene, reduce the release of HMGB1 protein in the liver, regulate liver macrophages to be an anti-inflammatory M2 phenotype, effectively reduce hepatic lobular inflammation and bullous steatosis in the liver, and restore the liver function of NASH model mice to a normal level. After 8 weeks of combined treatment with mLNP-siHMGB1 and DHA, the liver function of NASH model mice recovered rapidly and the hepatic steatosis returned to normal level. In view of inflammation, a key factor in the progression of NASH, we provided an actively targeted siRNA delivery system in this study, and clarified the important role of the delivery system in phenotypic regulation of liver macrophages in NASH. In addition, we also demonstrated the effectiveness of DHA co-administration in NASH treatment. This study provided a useful idea and scientific basis for the development of therapeutic strategies for NASH in the future. [Display omitted] •HMGB1, an inflammatory factor produced by macrophages, can promote NASH progression.•Mannose-modified HMGB1-siRNA loaded lipid nanoparticles were prepared to treat NASH.•They could silence HMGB1 protein, inhibit liver inflammation, and treat NASH.•DHA co-administration further improved the therapeutic effect on NASH.