Zhang Jinfang, Shen Hongwei, Xu Jiaojiao, Liu Li, Tan Jingwen, Li Minghao, Xu Nan, Luo Shenggen, Wang Jing, Yang Fan, Tang Jie, Li Qinghua, Wang Yiting, Yu Lei, Yan Zhiqiang
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.
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.
ACS Nano. 2020 May 26;14(5):6305-6322. doi: 10.1021/acsnano.0c02633. Epub 2020 May 11.
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 (CSRNLIDC)-modified and HMGB1-siRNA-loaded stable nucleic acid lipid nanoparticles (HMGB1-siRNA@SNALP-pPB) 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 (HSP47-siRNA@SNALP-pPB), which have only an antifibrotic effect without an anti-inflammatory effect, was used as control. The results demonstrated that HMGB1-siRNA@SNALP-pPB 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. HMGB1-siRNA@SNALP-pPB showed a stronger therapeutic effect on liver cirrhosis than HSP47-siRNA@SNALP-pPB. 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.
以往关于肝硬化治疗的研究一直聚焦于如何抑制肝纤维化，却忽视了肝脏炎症这一促进肝硬化的关键潜在因素。高迁移率族蛋白B1（HMGB1）是一种促炎因子和成纤维细胞趋化因子，可促进肝星状细胞（HSCs）增殖以及肝脏炎症和纤维化的发展，在肝硬化形成过程中起关键作用。在本研究中，我们制备了pPB肽（CSRNLIDC）修饰且负载HMGB1-siRNA的稳定核酸脂质纳米颗粒（HMGB1-siRNA@SNALP-pPB），通过其双重抗纤维化和抗炎活性有效治疗肝硬化。将仅具有抗纤维化作用而无抗炎作用的pPB肽修饰且负载热休克蛋白47（HSP47）-siRNA的稳定核酸脂质纳米颗粒（HSP47-siRNA@SNALP-pPB）用作对照。结果表明，HMGB1-siRNA@SNALP-pPB在pPB肽的介导下主动靶向HSCs，有效沉默HMGB1基因，抑制HSCs的活化和增殖，减少HMGB1蛋白的释放，抑制肝脏中的胶原沉积和纤维化形成，并显著延长肝硬化小鼠模型的存活时间。HMGB1-siRNA@SNALP-pPB对肝硬化的治疗效果比HSP47-siRNA@SNALP-pPB更强。本研究基于双重抗纤维化和抗炎作用为肝硬化治疗提供了一种主动靶向的siRNA递送系统。此外，本研究阐明了除肝纤维化外炎症问题在肝硬化治疗中的作用，为未来肝硬化治疗策略的制定提供了有益思路和科学依据。
