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      Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis.

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          Abstract

          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.

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          Author and article information

          Journal
          J Control Release
          Journal of controlled release : official journal of the Controlled Release Society
          Elsevier BV
          1873-4995
          0168-3659
          March 2022
          : 343
          Affiliations
          [1 ] Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
          [2 ] Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: zqyan@sat.ecnu.edu.cn.
          Article
          S0168-3659(22)00052-9
          10.1016/j.jconrel.2022.01.038
          35092721
          615a61ee-2756-4870-ba0d-d9f323f46d0e
          History

          HMGB1 siRNA,Macrophages,Mannose receptor,NASH,Stable nucleic acid lipid nanoparticles

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