Oligocopper-Loaded Lipoic Acid Nanoparticles Promote Mitochondrial Protein Lipoylation for Augmented Cuproptosis...

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 IC₅₀ 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.