MnO2 nanozyme with lanthanide-based radiosensitization for advanced radiotherapy by tumor microenvironment triggering STING pathway activation

Radiotherapy, being a primary approach for cancer treatment, is plagued by systemic toxicity resulting from high-dose radiation, as well as radioresistance due to the unique characteristics of tumor microenvironment (TME), including hypoxia, high expression of reducing substances and immunosuppression. The collaboration between radiosensitization and manipulation of the TME has the potential to surmount the challenges associated with advanced radiotherapy. Here, we propose a radiosensitization approach that involves enhancing X-ray deposition through physical means, while simultaneously reducing radioresistance and activating the stimulator of interferon genes (STING) pathway using a nanozyme that mimics natural enzymatic activity. This is achieved by fabricating a lanthanide ion radiosensitizer-based multifunctional enzyme activity nanoplatform, MnO2@NaGdF4:5%Nd@NaYbF4:20%Nd(MN). In the TME, the NaGdF4:5%Nd@NaYbF4:20%Nd radiosensitizer sensitizes cancer cells to X-ray. The MnO2 exhibits catalase-like (CAT) activity, enabling it to catalyze the conversion of H2O2 into O2, thereby alleviating tumor hypoxia. Additionally, MnO2 reacts with overexpressed glutathione (GSH) by glutathione oxidase-like (GSHOx) activity to generate Mn2+ ions. This reaction optimizes the function of ·OH, which can also be produced by the released Mn2+ through a Fenton-like reaction. The DNA damage caused by ·OH can be detected by cyclic GMP-AMP synthase (cGAS) to activate STING pathway, which also can be activated by the released Mn2+ ion. Through a two-pronged strategy with radical oxygen species overproduction and STING pathway activation, the lanthanide doped radiosensitizer-based MN can be relied upon to deliver highly effective radiotherapy.