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.

中文翻译：

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具有 Toll 样受体 4 shRNA 的肝星状细胞特异性脂质体可减轻肝纤维化

肝星状细胞（HSCs）在肝纤维化的发生中起重要作用，可以通过抑制和逆转 HSC 活化来治疗。RNA干扰介导的TLR4基因沉默可能是肝纤维化的潜在治疗方法。这种方法的关键挑战是缺乏用于将 RNAi 引入靶细胞的有效传递系统。HSCs 具有增强的维生素 A 摄入能力，因为它们含有视黄酸受体 (RAR)。在目前的研究中，我们开发了用维生素 A 修饰的阳离子脂质体，以提高 HSC 递送载体的特异性。这项研究的结果表明，在体外和体内条件下，与未偶联的阳离子脂质体相比，VitA 偶联的阳离子脂质体更有效地将 TLR4 shRNA 递送至 aHSC。此外，从本研究的结果可以看出，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 HSC 活化并减轻肝纤维化。因此，用 TLR4-shRNA 包裹的 VitA 偶联脂质体可能被证明是肝纤维化的有效治疗剂。