Tumor Microenvironment-Activable Multifunctional Nanocomposite for Tumor Therapy via Enhanced Cuproptosis, Ferroptosis, and Biochemical Activation

A trimetallic nanocomposite MnCuSn decorated with bovine serum albumin and folic acid (MnCuSn@FA@BSA, denoted as MCSFB) was fabricated for synergistic cancer treatment. The MCSFB harboring multivalent elements exhibited outstanding peroxidase-like activity and glutathione depletion capacity, resulting in the accumulation of •OH and effective immunogenic cell death. Furthermore, the Mn2+ isolated from MCSFB could facilitate the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and promote dendritic cell maturation and macrophage M1 repolarization. Additionally, excessive Cu could cause the decline of iron–sulfur cluster proteins and ultimately trigger cuproptosis. Mechanistic studies revealed that MCSFB-mediated tumor cell death was involved with the synergistic effect of ferroptosis, cuproptosis, and cyclic GMP-AMP synthase/stimulator of interferon genes activation. The in vivo results demonstrated that the proliferation of primary and metastatic tumors could be suppressed efficiently. The fabricated MCSFB could serve as a simple nanoplatform for multifunctional synergistic cancer therapy.