Microenvironment-induced programmable nanotherapeutics restore mitochondrial dysfunction for the amelioration of non-alcoholic fatty liver disease

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia Pub Date : 2025-03-01 DOI:10.1016/j.actbio.2025.01.019

Jun Zhang , Wenyi Yang , Yue Zhu , Zhanbin Li , Yin Zheng , Yufei Zhang , Weisong Gao , Xinge Zhang , Zhongming Wu , Ling Gao

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引用次数: 0

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disorder with severe complications. Mitochondrial dysfunction due to over-opening of the mitochondrial permeability transition pore (mPTP) in liver cells plays a central role in the development and progression of NAFLD. Restoring mitochondrial function is a promising strategy for NAFLD therapy. Herein, we designed and developed a microenvironment-induced programmable nanotherapeutic to restore mitochondrial function and ameliorate NAFLD. cyclosporine (Cyclosporine capsules) A (CsA), as a highly effective inhibitors of the opening of mPTP, was chosen in the present work. Nanotherapeutics were prepared by assembling two structurally simple multifunctional glucosamine derivatives: dextran-grafted galactose (Dex-Gal) and Dex-triphenylphosphine (Dex-TPP). Galactose units in the nanotherapeutics guide the hepatocyte-specific uptake. Detachment of galactose from acidic lysosomes via Schiff base cleavage exposes the TPP moieties, which subsequently steers the nanotherapeutics to escape from lysosomes and target mitochondria through an enhanced positive charge, enabling precise in situ drug delivery. Simultaneously, the nanotherapeutics improved mitochondrial dysfunction by inhibiting palmitic acid-induced opening of the mitochondrial permeability transition pore in HepG2 cells, maintaining mitochondrial membrane potential, and decreasing reactive oxygen species production. Furthermore, CsA@Dex-Gal/TPP accumulated in the livers of NAFLD mice, restored mitochondrial autophagy, regulated abnormalities in glucose and lipid metabolism, and improved hepatic lipid deposition. This study offers a new cascading strategy for targeting liver cell mitochondria to treat NAFLD and other mitochondria-associated diseases.

Statement of Significance

We design microenvironment-induced programmable nanotherapeutics for NAFLD

Nanotherapeutics has the capabilities of lysosomal escape and mitochondrial targeting

Nanotherapeutics improves mitochondrial dysfunction and ameliorates NAFLD

This study offers a new cascading strategy for other mitochondria-associated diseases

Abstract Image

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微环境诱导的可编程纳米疗法可恢复线粒体功能障碍，从而改善非酒精性脂肪肝。

非酒精性脂肪性肝病（NAFLD）是一种具有严重并发症的代谢性肝脏疾病。肝细胞线粒体通透性过渡孔（mPTP）过度开放导致的线粒体功能障碍在NAFLD的发生和发展中起着核心作用。恢复线粒体功能是NAFLD治疗的一个很有前途的策略。在此，我们设计并开发了一种微环境诱导的可编程纳米疗法，以恢复线粒体功能并改善NAFLD。本研究选择环孢素A （Cyclosporine A, CsA）作为mPTP开放的高效抑制剂。通过组装两种结构简单的多功能葡萄糖胺衍生物：葡聚糖接枝半乳糖（Dex-Gal）和dex -三苯基膦（Dex-TPP）制备纳米治疗药物。纳米治疗药物中的半乳糖单位指导肝细胞特异性摄取。通过希夫碱裂解从酸性溶酶体分离半乳糖，暴露TPP部分，随后引导纳米治疗药物通过增强的正电荷逃离溶酶体并靶向线粒体，从而实现精确的原位药物递送。同时，纳米疗法通过抑制棕榈酸诱导的HepG2细胞线粒体通透性过渡孔的打开、维持线粒体膜电位和减少活性氧的产生来改善线粒体功能障碍。此外，CsA@Dex-Gal/TPP在NAFLD小鼠肝脏中积累，恢复线粒体自噬，调节糖脂代谢异常，改善肝脏脂质沉积。这项研究为靶向肝细胞线粒体治疗NAFLD和其他线粒体相关疾病提供了一种新的级联策略。意义声明：我们设计了微环境诱导的可编程纳米治疗NAFLD的纳米治疗药物，纳米治疗药物具有溶酶体逃逸和线粒体靶向的能力，纳米治疗药物改善线粒体功能障碍并改善NAFLD，这项研究为其他线粒体相关疾病提供了新的级联策略。

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

Acta Biomaterialia 工程技术-材料科学：生物材料

CiteScore

16.80

自引率

3.10%

发文量

776

审稿时长

30 days

期刊介绍： Acta Biomaterialia is a monthly peer-reviewed scientific journal published by Elsevier. The journal was established in January 2005. The editor-in-chief is W.R. Wagner (University of Pittsburgh). The journal covers research in biomaterials science, including the interrelationship of biomaterial structure and function from macroscale to nanoscale. Topical coverage includes biomedical and biocompatible materials.

文献相关原料

公司名称

产品信息

麦克林

sodium periodate (NaIO4)

阿拉丁

sodium borohydride (NaBH4)

阿拉丁

Cyclosporin A (CsA)