Copper phosphate-rotenone nanocomposites for tumor therapy through autophagy blockage-enhanced triphosadenine supply interruption and lipid peroxidation accumulation

Malignant tumor cells feature rapid metabolism and proliferation that need a large amount of energy to maintain these physiological activities. Blocking energy supply through mitochondria dysfunction is an alternative strategy but is hindered by the limited blockage efficacy and the repairation of cytoprotective autophagy. Herein, a novel kind of bull serum albumin (BSA)-coated rotenone (RO)-copper phosphate (CuPi) nanocompsites was prepared for tumor therapy through autophagy blockage-enhanced triphosadenine (ATP) supply interruption and lipid peroxidation (LPO) accumulation. When internalization by tumor cells, these formed BSA-RO-CuPi nanoparticles (NPs) degraded to release RO, Cu2+, and PO43-. RO acts on mitochondrial complex I and reduces the activity of Fe-S clusters, and Cu2+ is reduced into Cu+ by ferredoxin 1 (FDX1) to induce dihydrolipoamide S-acetyltransferase (DLAT) aggregation. Thus, mitochondria function is severely damaged to cut off ATP supply. Meanwhile, Cu2+ depletes glutathione (GSH) through a redox reaction and produces hydroxyl radicals through the Fenton-like reaction, inducing the generation of LPO. Importantly, PO43- weakens lysosomal acidity to disrupt the autophagy capacity of tumor cells, resulting in damage accumulation. In vivo data demonstrated that these developed BSA-RO-CuPi NPs show desirable antitumor capacity and emphasize the importance of mitochondria dysfunction in tumor treatment applications.