Non-alcoholic steatohepatitis (NASH), now known as metabolic dysfunction-associated steatohepatitis (MASH), involves oxidative stress caused by the overproduction of reactive oxygen species (ROS). Small-molecule antioxidants have not been approved for antioxidant chemotherapy because of severe adverse effects that collapse redox homeostasis, even in healthy tissues. To overcome these disadvantages, we have been developing poly(ethylene glycol)--poly(cysteine) (PEG--PCys)-based self-assembling polymer nanoparticles (Nanoes), releasing Cys after in vivo degradation by endogenous enzymes, to obtain antioxidant effects without adverse effects. However, a comprehensive investigation of the effects of polymer design on therapeutic outcomes has not yet been conducted to develop our Nano system for antioxidant chemotherapy. In this study, we synthesized different poly(-cysteine) (PCys) chains whose sulfanyl groups were protected by -butyl thiol (SBu) and butyryl (Bu) groups to change the reactivity of the side chains, affording Nano and Nano, respectively. To elucidate the importance of the polymer design, these Nanoes were orally administered to MASH model mice as a model of oxidative stress-related diseases. Consequently, the acyl-protective Nano significantly suppressed hepatic lipid accumulation and oxidative stress compared to Nano. Furthermore, we substantiated that shorter PCys were much better than longer PCys for therapeutic outcomes and the effects related to the liberation properties of Cys from these nanoparticles. Owing to its antioxidant functions, Nanoes also significantly attenuated hepatic inflammation and fibrosis in the MASH mouse model.

中文翻译：

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基于聚乙二醇-嵌段-聚半胱氨酸嵌段共聚物的自组装抗氧化纳米颗粒治疗代谢功能障碍相关的脂肪性肝炎

非酒精性脂肪性肝炎 (NASH)，现在称为代谢功能障碍相关脂肪性肝炎 (MASH)，涉及由活性氧 (ROS) 过度产生引起的氧化应激。小分子抗氧化剂尚未被批准用于抗氧化化疗，因为其严重的副作用会破坏氧化还原稳态，甚至在健康组织中也是如此。为了克服这些缺点，我们开发了聚乙二醇-聚半胱氨酸（PEG--PCys）基自组装聚合物纳米颗粒（Nanoes），在体内被内源酶降解后释放Cys，获得抗氧化剂效果，无不良影响。然而，尚未对聚合物设计对治疗结果的影响进行全面研究，以开发我们用于抗氧化化疗的纳米系统。在本研究中，我们合成了不同的聚（半胱氨酸）（PCys）链，其硫基受到丁基硫醇（SBu）和丁酰（Bu）基团的保护，以改变侧链的反应性，分别得到Nano和Nano。为了阐明聚合物设计的重要性，这些纳米颗粒被口服给 MASH 模型小鼠作为氧化应激相关疾病的模型。因此，与 Nano 相比，酰基保护性 Nano 显着抑制了肝脏脂质积累和氧化应激。此外，我们证实较短的 PCys 比较长的 PCys 的治疗效果和与从这些纳米颗粒中释放 Cys 特性相关的效果要好得多。由于其抗氧化功能，Nanoes 还显着减轻了 MASH 小鼠模型中的肝脏炎症和纤维化。