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Liver-Targeted siRNA Lipid Nanoparticles Treat Hepatic Cirrhosis by Dual Antifibrotic and Anti-inflammatory Activities.

Authors
  • Zhang, Jinfang1
  • Shen, Hongwei1
  • Xu, Jiaojiao1
  • Liu, Li1
  • Tan, Jingwen1
  • Li, Minghao1
  • Xu, Nan1
  • Luo, Shenggen1
  • Wang, Jing1
  • Yang, Fan2
  • Tang, Jie2
  • Li, Qinghua3
  • Wang, Yiting1
  • Yu, Lei1
  • Yan, Zhiqiang1
  • 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, People's Republic of China. , (China)
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, People's Republic of China. , (China)
  • 3 Department of Hepatology and Pancreatology, Shanghai East Hospital, Tongji University, Shanghai 200120, People's Republic of China. , (China)
Type
Published Article
Journal
ACS Nano
Publisher
American Chemical Society
Publication Date
May 11, 2020
Identifiers
DOI: 10.1021/acsnano.0c02633
PMID: 32378877
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Previous studies on the treatment of hepatic cirrhosis have been focusing on how to inhibit liver fibrosis, while ignoring liver inflammation, a key and underlying factor that promotes cirrhosis. High mobility group box-1 (HMGB1) protein, a pro-inflammatory factor and fibroblast chemokine, can promote the proliferation of hepatic stellate cells (HSCs) and the development of hepatic inflammation and fibrosis, playing a key role in cirrhosis formation. In this study, we prepared pPB peptide (C*SRNLIDC*)-modified and HMGB1-siRNA-loaded stable nucleic acid lipid nanoparticles ([email protected]) to effectively treat hepatic cirrhosis by their dual antifibrotic and anti-inflammatory activities. The pPB peptide-modified and heat shock protein 47 (HSP47)-siRNA-loaded stable nucleic acid lipid nanoparticles ([email protected]), which have only an antifibrotic effect without an anti-inflammatory effect, was used as control. The results demonstrated that [email protected] were actively targeted to HSCs by the mediation of pPB peptide, effectively silenced the HMGB1 gene, inhibited the activation and proliferation of HSCs, reduced the release of HMGB1 protein, inhibited collagen deposition and fibrosis formation in the liver, and significantly prolonged the survival time of cirrhotic mice models. [email protected] showed a stronger therapeutic effect on liver cirrhosis than [email protected] This study provides an actively targeted siRNA delivery system for cirrhosis treatment based on the dual antifibrotic and anti-inflammatory effects. In addition, this study clarified the role of inflammatory problems in cirrhosis treatment in addition to liver fibrosis, providing a useful idea and scientific basis for the development of cirrhosis treatment strategies in the future.

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