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

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

doi:10.1016/j.actbio.2025.01.019

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

Acta Biomater. 2025 Jan 11:S1742-7061(25)00027-3. doi: 10.1016/j.actbio.2025.01.019. Online ahead of print.

Authors

Jun Zhang¹, Wenyi Yang¹, Yue Zhu¹, Zhanbin Li¹, Yin Zheng², Yufei Zhang³, Weisong Gao², Xinge Zhang³, Zhongming Wu⁴, Ling Gao⁵

Affiliations

¹ 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.
² 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.
³ Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
⁴ 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. Electronic address: wuzhongming@sph.com.cn.
⁵ 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; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China. Electronic address: linggao@sdu.edu.cn.

PMID: 39805524
DOI: 10.1016/j.actbio.2025.01.019

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 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.

Keywords: mitochondrial function; mitochondrial targeting; nonalcoholic fatty liver disease; programmable nanotherapeutics.