Biodegradable doxorubicin-loaded ferric phosphate nanosheets for specific tumor elimination through autophagy inhibition-enhanced apoptosis/ferroptosis pathway

Killing tumor cells through apoptosis and/or ferroptosis pathways has been extensively explored for tumor therapy. However, the therapeutic efficacy is always impaired by the autophagy-mediated self-repairing capacity of tumor cells. Herein, a novel autophagy inhibition-enhanced apoptosis/ferroptosis strategy was developed for synergistic tumor elimination, which was realized through the doxorubicin (DOX)-loaded ferric phosphate nanosheets. When located in tumor regions, these nanosheets can be specifically degraded under the stimulation of tumor microenvironment. The released DOX can not only damage DNA to induce cell apoptosis directly but also up-regulate intracellular hydrogen peroxide level. Free Fe2+ can be generated from Fe3+ through intracellular over-expressed glutathione-participated redox reaction, which can further react with hydrogen peroxide through the Fenton reaction to produce highly oxidative hydroxyl radicals. This redox process simultaneously breaks the antioxidant capacity of tumor cells through the depletion of glutathione and the inactivation of intracellular antioxidase glutathione peroxidase 4, promoting the generation and accumulation of lipid peroxidation to cause tumor ferroptosis. Especially, PO43− disrupts the pH balance in lysosomes by forming conjugated acid anions to disable the self-repairing capacity of tumor cells, enhancing the antitumor therapeutic effect. This work offers a promising method with desirable biocompatibility for specific tumor elimination through autophagy inhibition-enhanced apoptosis/ferroptosis strategy.