PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-09-09 DOI:10.1515/biol-2022-0952

Yun Wang, Yi Xu, Tun Zhao, Ya-Jun Ma, Wei Qin, Wen-Li Hu

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Abstract

Intensive care unit-acquired weakness (ICU-AW) is prevalent in critical care, with limited treatment options. Certain microRNAs, like miR-542, are highly expressed in ICU-AW patients. This study investigates the regulatory role and mechanisms of miR-542 in ICU-AW and explores the clinical potential of miR-542 inhibitors. ICU-AW models were established in C57BL/6 mice through cecal ligation and puncture (CLP) and in mouse C2C12 myoblasts through TNF-α treatment. In vivo experiments demonstrated decreased muscle strength, muscle fiber atrophy, widened intercellular spaces, and increased miR-542-3p/5p expression in ICU-AW mice model. In vitro experiments indicated suppressed ATG5, ATG7 and LC3II/I, elevated MDA and ROS levels, decreased SOD levels, and reduced MMP in the model group. Similar to animal experiments, the expression of miR-542-3p/5p was upregulated. Gel electrophoresis explored the binding of polyethyleneimine/mesoporous silica nanoparticles (PEI/MMNs) to locked nucleic acid (LNA) miR-542 inhibitor (LNA-542). PEI/MMNs@LNA-542 with positive charge (3.03 ± 0.363 mV) and narrow size (206.94 ± 6.19 nm) were characterized. Immunofluorescence indicated significant internalization with no apparent cytotoxicity. Biological activity, examined through intraperitoneal injection, showed that PEI/MMNs@LNA-542 alleviated muscle strength decline, restored fiber damage, and recovered mitochondrial injury in mice. In conclusion, PEI/MMNs nanoparticles effectively delivered LNA-542, targeting ATG5 to inhibit autophagy and alleviate mitochondrial damage, thereby improving ICU-AW.

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PEI/MMNs@LNA-542纳米粒子通过靶向抑制自噬和保护线粒体缓解重症监护室获得性乏力

重症监护室获得性乏力（ICU-AW）在重症监护中很普遍，但治疗方法却很有限。某些微RNA，如miR-542，在ICU-AW患者中高度表达。本研究调查了 miR-542 在 ICU-AW 中的调控作用和机制，并探索了 miR-542 抑制剂的临床潜力。通过盲肠结扎和穿刺（CLP）在 C57BL/6 小鼠中建立了 ICU-AW 模型，通过 TNF-α 处理在小鼠 C2C12 肌母细胞中建立了 ICU-AW 模型。体内实验表明，ICU-AW 小鼠模型的肌力下降、肌纤维萎缩、细胞间隙增宽，miR-542-3p/5p 表达增加。体外实验表明，模型组的 ATG5、ATG7 和 LC3II/I 受抑制，MDA 和 ROS 水平升高，SOD 水平降低，MMP 减少。与动物实验相似，miR-542-3p/5p 的表达上调。凝胶电泳探讨了聚乙烯亚胺/介孔二氧化硅纳米颗粒（PEI/MMNs）与锁定核酸（LNA）miR-542抑制剂（LNA-542）的结合。PEI/MMNs@LNA-542 带有正电荷（3.03 ± 0.363 mV），尺寸较窄（206.94 ± 6.19 nm）。免疫荧光显示其内化效果显著，无明显细胞毒性。通过腹腔注射进行的生物活性研究表明，PEI/MMNs@LNA-542 可缓解小鼠肌肉力量下降、恢复纤维损伤和线粒体损伤。总之，PEI/MMNs 纳米颗粒能有效递送 LNA-542，靶向 ATG5 抑制自噬，减轻线粒体损伤，从而改善 ICU-AW。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.