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

作者：Ying Chen, Junyu Wang, Yaya Zheng, Jun Zhang, Juan Wang, Haoran Ye, Ling Tao, Yongchao Yao, Xinghong Luo, Yang Ding, Xiangchun Shen · 发表于：Small · 年份：2025 · DOI：10.1002/smll.202501259 · 被引用次数：8 · 研究领域：Biochemical Acid Research Studies、Coenzyme Q10 studies and effects、Mitochondrial Function and Pathology

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.