Fe3S4 nanozyme inhibits tumor growth by synergistic effects of ferroptosis and apoptosis

Although apoptosis therapy offers huge potential for cancer treatment, its efficacy is still limited by KRAS mutations and insufficient H2O2 supply in tumor cells and considered a critical issue to overcome. Herein, we developed a novel peroxidase nanozyme (Fe3S4) with excellent H2O2 affinity and can effectively catalyze ·OH generation from H2O2, which not only induces apoptosis but also activates ferroptosis of tumor cells. Interestingly, Fe3S4 nanozyme administration disturbs iron metabolism, and causes abundant Fe2+ accumulation in tumor cells, which amplifies Fenton reaction and further promotes tumor cell apoptosis and ferroptosis. Additionally, Fe3S4 nanozyme possesses ultrahigh glutathione peroxidase-like activity and can convert GSH into GSSG. The depletion of GSH sensitizes tumor cells to Fe3S4-mediated ferroptosis. With the assistance of ferroptosis, apoptosis activating by Fe3S4 can more effectively to inhibit tumor growth, and even apoptosis-resistant tumors are no different. Thus, this strategy provides a superior platform for strengthening the therapeutic effect of nanozymes.