NaErF4-Based Nanocarrier for Enhanced Ferroptosis Therapy of Cancer

To improve the treatment efficiency of ferroptosis and accurately monitor the therapy process, we developed small-sized upconversion nanoparticles (UCNPs) by a simple one-step solvothermal method. On this basis, a facile strategy is reported to construct mesoporous SiO2-coated UCNPs as the nanocarrier to load dual drugs of MnO2 and methylene blue (MB) photosensitizer for hypoxic tumor theranostic. Due to the components of high charge elements, the synthetic NaErF4:Yb,Gd,Eu@mSiO2/MnO2/MB@FA (UPSMF/MB, FA = folic acid) exhibited radiosensitization function. Emitting strong red upconversion luminescence (UCL) excited the encapsulated MB to initiate photodynamic therapy (PDT). In addition, UPSMF/MB released green UCL imaging in vivo, so as to trace drug distribution and achieve accurate theranostic. In tumor microenvironment, the loaded MnO2 possessed catalase-like (CAT) catalytic activity, which could effectively decompose excessive H2O2 into O2, thus alleviating hypoxia in the tumor area and promoting PDT and radiotherapy (RT) to generate reactive oxygen species (ROS). Furthermore, MnO2 had excellent glutathione peroxidase (GPx)-like activity, which could effectively decompose intracellular over-expressed glutathione (GSH), thus causing lipid peroxide (LPO) accumulation and inducing ferroptosis. In situ ROS generation by PDT and RT further promoted the accumulation of intracellular LPO. Cytotoxicity assay revealed that the apoptosis rate of UPSMF/MB promoted by RT and PDT was 79.76%, which was 46% higher than that of solo ferroptosis induced by UPSMF. Notably, in vivo results illustrated that the tumor inhibition rate of UPSMF/MB could be increased to 83.4% under the triple effects of RT, PDT, and ferroptosis with negligible side effects to normal tissues. This work paves a way to enhance the efficacy of ferroptosis-based cancer therapy by associating PDT with RT.