A gold-doped Thionin carbon nanozyme induces ferroptosis to boost chemo/photo-dynamic therapy

Both reactive oxygen species (ROS) and ferroptosis are recognized for their pivotal regulatory roles in tumor survival. However, the hypoxic and high glutathione (GSH) environment within tumors presents a significant barrier to these therapeutic strategies. In this study, we have developed a novel gold-doped carbon-dotted nanozyme (Au-CDs) exhibiting multi-enzyme-like activities, which effectively alleviate tumor hypoxia and achieve the self-enhanced combined treatment effect of chemodynamic (CDT) and photodynamic therapy (PDT) independent of oxygen. Furthermore, it effectively depletes GSH to achieve a robust ROS amplifier. The synthesized Au-CDs have demonstrated efficacy in inducing ROS release, promoting lipid peroxidation accumulation and reducing the GSH levels, resulting in the inhibited proliferation of tumor cells in vitro . In a xenograft model, Au-CDs effectively inhibited the tumor growth of nude mice. In terms of molecular mechanism, Au-CDs were able to upregulate transferrin receptor 1 (TFR1) expression and increase the Fe 2+ content, and finally to induce the tumor related ferroptosis, which was more significant in combination with self-enhanced PDT. The biosafety assessment demonstrated Au-CDs had no significant toxicity in the major organs of mice. Taken together, these findings suggested Au-CDs as a novel and safe nanozyme have great potential to be utilized in combination therapies in cancer.