Nanozyme as Tumor Energy Homeostasis Disruptor to Augment Cascade Catalytic Therapy

Breaking the balance of the tumor microenvironment and reshaping it sustainably remain major challenges in lung cancer treatment. Here, a "tumor energy homeostasis disruptor", the Cu₂O@Au nanozyme was developed, which exhibits excellent glucose oxidase-like activity, enabling it to be used for starvation therapy and as a mimic peroxidase for chemodynamic therapy (CDT), producing ^•OH. Cu₂O@Au nanozymes consume glucose at the tumor site to block the tumor's energy supply, produce H₂O₂ continuously, and lower the pH to enhance the efficiency of CDT, initiating a cascade reaction that leads to a storm of reactive oxygen species (ROS). Furthermore, Cu₂O@Au nanozyme consumes glutathione and reduces the expression of the SLC7A11 (<i>x</i>CT) protein to decrease cancer cell uptake of cysteine, further enhancing the burst of ROS, resulting in lipid peroxidation in tumor cells and ultimately leading to ferroptosis. The excellent photothermal performance of Cu₂O@Au can further enhance CDT. Additionally, Cu₂O@Au nanozyme also has computed tomography (CT) and photothermal imaging capabilities. In conclusion, Cu₂O@Au nanozymes, acting as tumor energy homeostasis disruptor, can effectively inhibit tumor growth and successfully achieve the synergistic effects of starvation therapy/CDT/photothermal therapy (PTT). This multifunctional nanozyme holds promise for providing valuable insights and therapeutic strategies for cancer treatment.