RESUMO
Despite the therapeutic response of ferroptosis in various tumors, ferroptosis resistance has been found in numerous studies, significantly hindering the progress of ferroptosis anti-tumor therapy. Herein, we propose a metal-rich cascade nanosystem (Simvastatin-HMPB-Mn@GOx) combined with the dual-pathway regulation of ferroptosis resistance and photothermal therapy for efficient tumor combination therapy. The manganese-bonded hollow mesoporous Prussian blue (HMPB-Mn) serves as the photothermal agent and metal donor, and dissociates multivalent metal ions Mn2+, Fe3+ and Fe2+ to consume glutathione and amplify the Fenton reaction. Glucose oxidase (GOx) absorbed serves as the converter to provide hydrogen peroxide (H2O2) for the cascade Fenton reaction, causing a high burst of hydroxyl radicals (ËOH) and lipid peroxidation. Simvastatin innovatively acts as a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) inhibitor to decrease the expression of coenzyme Q10 (CoQ10) and glutathione peroxidase 4 (GPX4), eventually defeating ferroptosis resistance. The nanosystem acted in both classical and non-classical ferroptosis pathways and showed significant ferroptosis- and hyperthermia-induced anti-tumor efficacy both in vitro and in vivo. Thus, this study offers a promising way for ferroptosis and phototherapy to achieve complete tumor regression.