Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
ACS Nano. 2023 Aug 8;17(15):14852-14870. doi: 10.1021/acsnano.3c03217. Epub 2023 Jul 25.
Chronic liver injury and inflammation triggered by metabolic abnormalities initiate the activation of hepatic stellate cells (HSCs), driving fibrosis and parenchymal dysfunction, culminating in disorders such as nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs capable of effectively treating NASH due to the challenges in addressing fibrosis and restoring extracellular matrix (ECM) homeostasis. We discovered a significant up-regulation of interleukin-11 (IL-11) in fibrotic livers using two well-established murine models of NASH. To leverage this signaling pathway, we developed a nanoparticle (NP)-assisted RNA interfering approach that specifically targets activated HSCs (aHSCs), blocking IL-11/ERK signaling to regulate HSC transdifferentiation along with fibrotic remodeling. The most potent NP, designated NP-AEAA, showed enhanced accumulation in fibrotic livers with NASH and was primarily enriched in aHSCs. We further investigated the therapeutic efficacy of aHSC-targeting NP-AEAA encapsulating small interfering RNA (siRNA) against or its cognate receptor (termed si@NP-AEAA or si@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both si@NP-AEAA and si@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, si@NP-AEAA exhibits a superior therapeutic effect over si@NP-AEAA, in terms of reducing liver steatosis and fibrosis as well as recovering liver function. These results constitute a targeted nanoparticulate siRNA therapeutic approach against the IL-11 signaling pathway of aHSCs in the fibrotic liver, offering a promising therapeutic intervention for NASH and other diseases.
慢性肝损伤和代谢异常引起的炎症会激活肝星状细胞（HSCs），导致纤维化和实质功能障碍，最终导致非酒精性脂肪性肝炎（NASH）等疾病。不幸的是，由于解决纤维化和恢复细胞外基质（ECM）平衡的挑战，目前尚无有效的药物可用于治疗 NASH。我们使用两种成熟的 NASH 小鼠模型发现，纤维化肝脏中白细胞介素 11（IL-11）显著上调。为了利用这条信号通路，我们开发了一种纳米颗粒（NP）辅助 RNA 干扰方法，该方法专门针对激活的 HSCs（aHSCs），阻断 IL-11/ERK 信号通路以调节 HSC 转分化和纤维化重塑。最有效的 NP 命名为 NP-AEAA，在 NASH 纤维化肝脏中的蓄积增强，并且主要富集于 aHSCs。我们进一步研究了靶向 aHSC 的 NP-AEAA 封装小干扰 RNA（siRNA）针对 或其同源受体 （分别称为 si@NP-AEAA 或 si@NP-AEAA）治疗纤维化和 NASH 的疗效。结果表明，si@NP-AEAA 和 si@NP-AEAA 均可有效抑制 HSC 激活，并在两种成熟的 NASH 小鼠模型中解决纤维化和炎症。值得注意的是，si@NP-AEAA 在减轻肝脂肪变性和纤维化以及恢复肝功能方面比 si@NP-AEAA 具有更好的治疗效果。这些结果构成了针对纤维化肝脏中 aHSCs 的 IL-11 信号通路的靶向纳米颗粒 siRNA 治疗方法，为 NASH 和其他疾病提供了一种有前景的治疗干预措施。
