Zhang Jun, Yang Wenyi, Zhu Yue, Li Zhanbin, Zheng Yin, Zhang Yufei, Gao Weisong, Zhang Xinge, Wu Zhongming, Gao Ling
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China.
Acta Biomater. 2025 Mar 1;194:323-335. doi: 10.1016/j.actbio.2025.01.019. Epub 2025 Jan 11.
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.
非酒精性脂肪性肝病（NAFLD）是一种伴有严重并发症的代谢性肝脏疾病。肝细胞中线粒体通透性转换孔（mPTP）过度开放导致的线粒体功能障碍在NAFLD的发生和发展中起核心作用。恢复线粒体功能是治疗NAFLD的一种有前景的策略。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来恢复线粒体功能并改善NAFLD。环孢素（环孢素胶囊）A（CsA）作为一种高效的mPTP开放抑制剂，被选用于本研究。纳米疗法通过组装两种结构简单的多功能葡糖胺衍生物制备而成：葡聚糖接枝半乳糖（Dex-Gal）和葡聚糖-三苯基膦（Dex-TPP）。纳米疗法中的半乳糖单元引导肝细胞特异性摄取。半乳糖通过席夫碱裂解从酸性溶酶体中脱离，暴露出三苯基膦部分，随后通过增强的正电荷引导纳米疗法从溶酶体中逃逸并靶向线粒体，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细胞线粒体通透性转换孔开放、维持线粒体膜电位和减少活性氧生成，改善了线粒体功能障碍。此外，CsA@Dex-Gal/TPP在NAFLD小鼠肝脏中蓄积，恢复线粒体自噬，调节糖脂代谢异常，并改善肝脏脂质沉积。本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。重要意义声明：我们设计用于NAFLD的微环境诱导的可编程纳米疗法 纳米疗法具有溶酶体逃逸和线粒体靶向能力 纳米疗法改善线粒体功能障碍并改善NAFLD 本研究为其他线粒体相关疾病提供了一种新的级联策略
