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journal article·2025-09Open access

Oligocopper‐Loaded Lipoic Acid Nanoparticles Promote Mitochondrial Protein Lipoylation for Augmented Cuproptosis Therapy

Ying Chen, Junyu Wang, Yaya Zheng, Jun Zhang, Juan Wang, Haoran Ye, Ling Tao, Yongchao Yao, Xinghong Luo, Yang Ding, Xiangchun Shen

Small· Volume 21· Issue 37
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Source abstract

Abstract

Abstract Cuproptosis is a modality of mitochondrial cell death driven by the binding of excess copper ions to the lipoic acid residues of dihydrolipoamide S‐acetyltransferase (DLAT) protein. However, copper levels are tightly regulated within cells. Herein, an oligocopper‐loaded lipoic acid nanoparticle (Cu@TcNAs) is reported that can promote mitochondrial DLAT protein lipoylation and realize augmented cuproptosis therapy. This nanoparticle contains only 5.75% copper (mostly reported to be > 20%) and incorporates acetylgalactosamine as a target ligand. This targeted delivery increased cellular uptake of Cu@TcNAs and facilitated the degradation product of lipoic acid nanoparticles (dihydrolipoic acid, DHLA) to modify lysine residues of mitochondrial proteins, resulting in a 1.86‐ and 1.52‐fold increase in lipoylated DLAT in HepG2 and 4T1 cells, respectively. These lipoylated DLATs enhance binding to released copper ions, promoting disulfide bond‐dependent aggregation of lipoylated DLAT and causing cuproptosis in HepG2 and 4T1 cells with corresponding IC 50 values as low as 12.50 and 8.70 µg mL −1 , respectively. In vivo studies showed Cu@TcNAs at a copper dose of 0.27 mg kg −1 (mostly reported to be > 1.0 mg kg −1 ) achieved tumor inhibition rates of 74.32% and 84.87% in HepG2 and 4T1 tumor‐bearing mice, respectively, demonstrating superior biosafety and significant clinical potential.
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Research context

Nanomaterials

OpenAlex topics: Biochemical Acid Research Studies · Coenzyme Q10 studies and effects · Mitochondrial Function and Pathology

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability) & School of Pharmaceutical Sciences Guizhou Medical University No. 6 Ankang Avenue, Guian New District Guiyang Guizhou 561113 China

The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education) & State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Guizhou Medical University No. 6 Ankang Avenue, Guian New District Guiyang Guizhou 561113 China

Precision Medicine Translational Research Center (PMTRC) West China Hospital Sichuan University No.37 Guoxue Lane, Wuhou District Chengdu Sichuan 610041 China

State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University No.639 Longmian Avenue Nanjing Jiangsu 210009 China

Funding

National Natural Science Foundation of China · Department of Education of Guizhou Province · National College Students Innovation and Entrepreneurship Training Program

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