Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
J Cell Mol Med. 2021 Jan;25(2):1299-1313. doi: 10.1111/jcmm.16209. Epub 2020 Dec 18.
The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.
肝星状细胞（HSCs）在肝纤维化的发生中起重要作用，可通过抑制和逆转 HSC 激活来治疗。RNA 干扰介导的 TLR4 基因沉默可能是肝纤维化的一种潜在治疗方法。该方法的关键挑战是缺乏有效的 RNAi 导入靶细胞的传递系统。HSCs 具有增强的维生素 A 摄取能力，因为它们含有视黄酸受体（RARs）。在本研究中，我们开发了用维生素 A 修饰的阳离子脂质体，以提高用于 HSCs 的递送载体的特异性。研究结果表明，与未偶联的阳离子脂质体相比，VitA 偶联的阳离子脂质体在体外和体内条件下更有效地将 TLR4 shRNA 递送至 aHSCs。此外，正如本研究结果所示，TLR4 基因沉默通过 NF-κB 转录失活、促炎细胞因子分泌和活性氧（ROS）合成抑制 HSCs 激活并减轻肝纤维化。因此，包封 TLR4-shRNA 的 VitA 偶联脂质体可能被证明是肝纤维化的有效治疗剂。
