Fe/Co bimetallic nanozyme disrupting tumorous Self-Regulatory pathways to potentiate ferroptosis

Ferroptosis presents a promising tumor therapy, particularly in overcoming apoptosis resistance. However, the robust internal regulatory mechanisms of tumor cells, notably their antioxidant defense, impede ferroptosis induction. Herein, a tumor self-regulatory blocking strategy assisted by a bimetallic nanozyme (Co-MIL) with multi-enzyme activity for interfering with antioxidant defense to achieve synergistically enhanced tumor therapy. The obtained Co-MIL with a Fe/Co ratio of around 14.4 is found to be capable of generating massive high cytotoxic reactive oxygen species (ROS) ascribed to the increased electron polarization distribution in the bimetallic structure. More importantly, Co-MIL could interfere antioxidant defense by disrupting the synergistic interaction among antioxidants glutathione (GSH), nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH), which could block GSH regeneration and damage mitochondrial energy metabolism to restrict the energy supply, deeply affecting the tumor cells' ability to regulate the redox homeostasis. In vitro and in vivo results demonstrated that Co-MIL inhibited the tumorous self-regulatory pathway and generated significant oxidative stress, ultimately leading to effective ferroptosis. This work presents a therapeutic strategy that leverages tumor self-regulation mechanisms, thereby addressing the challenges in existing treatments and significantly enhancing therapeutic efficacy.