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

Schematic representation of Au-CDs with anti-tumor efficacy by self-enhanced CDT and PDT combination to mediate ferroptosis. • The gold doping increased the CAT-like and POD-like enzymatic activities of carbon dots, demonstrating strong chemo-dynamic therapy capability. • Au-CDs can act as highly efficient photosensitizers, capable of generating singlet ox-ygen with production rate as high as 1.46. • Au-CDs are able to deplete glutathione in TME and decompose H 2 O 2 in TEM, pro-ducing O 2 and ROS, thereby achieving more effective CDT and PDT. • Au-CDs release ROS in TEM, mediate oxidative stress, promote lipid peroxidation, and upregulate the expression of TFR1 to facilitate the influx of Fe 2+ , thereby enhancing the process of ferroptosis in tumors. 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.