Riociguat 联合半乳糖聚乙二醇化胆红素多重纳米药物增强正弦灌注和抑制细胞凋亡可改善肝纤维化进程,Nano Letters

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Riociguat 联合半乳糖聚乙二醇化胆红素多重纳米药物增强正弦灌注和抑制细胞凋亡可改善肝纤维化进程
Nano Letters ( IF 9.6 ) Pub Date : 2023-05-08 , DOI: 10.1021/acs.nanolett.2c04726
Fenfen Li _{1,

2,

3} , Zhaoxia Cheng _{1,

2,

4} , Jingyi Sun _{1,

2} , Xiaoyu Cheng _{1,

2} , Chen Li _{1,

2} , Zhouliang Wu _{1,

2} , Feilong Qi _{1,

2} , Ying Zhao _{1,

2} , Guangjun Nie _{1,

2,

5}

Affiliation

慢性肝损伤和持续的伤口愈合导致细胞外基质 (ECM) 沉积和肝纤维化。肝脏中活性氧 (ROS) 的产生增加导致肝细胞凋亡和肝星状细胞 (HSC) 活化。在当前的研究中，我们描述了 riociguat 与定制设计的半乳糖聚乙二醇化胆红素纳米药物 (Sel@GBRNPs) 实现的正弦灌注增强和细胞凋亡抑制的组合策略。Riociguat 增强肝窦灌注并降低相关的 ROS 积累和纤维化肝脏的炎症状态。同时，靶向肝细胞的半乳糖聚乙二醇化胆红素清除过多的 ROS 并释放封装的 selonsertib。释放的 selonsertib 抑制凋亡信号调节激酶 1 (ASK1) 磷酸化，从而减轻肝细胞凋亡。ROS 和肝细胞凋亡的联合作用减弱了肝纤维化小鼠模型中 HSC 活化和 ECM 沉积的刺激。该工作为基于肝窦灌注增强和细胞凋亡抑制的肝纤维化治疗提供了一种新策略。

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The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor-designed galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactose-PEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

更新日期：2023-05-08

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