Efficient Magnetic Nanocatalyst-Induced Chemo- and Ferroptosis Synergistic Cancer Therapy in Combination with T-T Dual-Mode Magnetic Resonance Imaging Through Doxorubicin Delivery.

Excessive iron ions in cancer cells can catalyze HO into highly toxic OH and then promote the generation of reactive oxygen species (ROS), inducing cancer ferroptosis. However, the efficacy of the ferroptosis catalyst is still insufficient because of low Fe(II) release, which severely limited its application in clinic. Herein, we developed a novel magnetic nanocatalyst for MRI-guided chemo- and ferroptosis synergistic cancer therapies through iRGD-PEG-ss-PEG-modified gadolinium engineering magnetic iron oxide-loaded Dox (ipGdIO-Dox). The introduction of the gadolinium compound disturbed the structure of ipGdIO-Dox, making the magnetic nanocatalyst be more sensitive to weak acid. When ipGdIO-Dox entered into cancer cells, abundant Fe(II) ions were released and then catalyzed HO into highly toxic OH, which would elevate cellular oxidative stress to damage mitochondria and cell membranes and induce cancer ferroptosis. In addition, the iRGD-PEG-ss-PEG chain coated onto the nanoplatform was also broken by high expression of GSH, and then, the Dox was released. This process not only effectively inhibited DNA replication but also further activated cellular ROS, making the nanoplatform achieve stronger anticancer ability. Besides, the systemic delivery of ipGdIO-Dox significantly enhanced the T- and T-weighted MRI signal of the tumor, endowing accurate diagnostic capability for tumor recognition. Therefore, ipGdIO-Dox might be a promising candidate for developing an MRI-guided chemo- and ferroptosis synergistic theranostic system.