Sorafenib-Loaded Copper Phosphate Nanoparticles with Redox Balance Disruption and Autophagy Blockage Capacities for Enhanced Tumor Ferroptosis and Cuproptosis

Abstract Utilizing the inherent properties of copper could realize tumor therapy through ferroptosis and cuproptosis pathways. However, the therapeutic efficiency is always compromised by the intracellular antioxidant ability and cytoprotective autophagy process. Herein, enhanced tumor ferroptosis/cuproptosis was realized using copper phosphate-sorafenib-polyacrylic acid (CuPi-SRF-PAA) nanoparticles (NPs). They could degrade to release Cu2+, SRF, and PO43– under acidic conditions. The released Cu2+ not only promotes lipid hydroperoxides generation through a Fenton-like reaction to cause ferroptosis but also damages mitochondrial dihydrolipoamide S-acetyltransferase to induce cuproptosis. Meanwhile, SRF inhibits glutathione generation through deactivating system xc– to realize redox balance disruption, and PO43– causes lysosomal deacidification to achieve autophagy blockage, enhancing the efficacy of ferroptosis and cuproptosis. In vitro and in vivo data demonstrated that these CuPi-SRF-PAA NPs could achieve effective tumor suppression with high biocompatibility. This work highlights the key roles of combining redox balance disruption and autophagy blockage in tumor therapy.