肝星状细胞
纤维化
转分化
癌症研究
小干扰RNA
炎症
肝纤维化
非酒精性脂肪肝
基因沉默
脂肪变性
清道夫受体
生物
细胞生物学
药理学
医学
脂肪肝
免疫学
转染
病理
细胞培养
内分泌学
干细胞
生物化学
脂蛋白
遗传学
疾病
胆固醇
基因
作者
Chenshuang Zhang,Yilong Teng,Fengqiao Li,William Ho,Xin Bai,Xiaoyang Xu,Xue‐Qing Zhang
出处
期刊:ACS Nano
[American Chemical Society]
日期:2023-07-25
卷期号:17 (15): 14852-14870
被引量:7
标识
DOI:10.1021/acsnano.3c03217
摘要
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 IL11 or its cognate receptor IL11ra1 (termed siIL11@NP-AEAA or siIL11ra1@NP-AEAA, respectively) for resolving fibrosis and NASH. Our results demonstrate that both siIL11@NP-AEAA and siIL11ra1@NP-AEAA effectively inhibit HSC activation and resolve fibrosis and inflammation in two well-established murine models of NASH. Notably, siIL11ra1@NP-AEAA exhibits a superior therapeutic effect over siIL11@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.
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