Iron-doped Zif-8 nanoplatform for MRI-guided synergistic microwave thermal/chemodynamic therapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC), a highly refractory malignancy characterized by aggressive clinical behavior, poses a significant therapeutic challenge due to its resistance to conventional treatments. While microwave thermal therapy (MWTT) emerges as a promising modality for TNBC treatment through deep-tissue penetration and uniform energy delivery, its reliance on prolonged hyperthermia exposure risks collateral damage to adjacent healthy tissues. Herein, we present a rationally engineered iron-doped zeolitic imidazolate framework-8 nanoplatform (Fe@Zif-8). This study aimed to develop a theranostic agent for MRI-guided combination therapy by pursuing the following objectives: (1) synthesizing and characterizing Fe-doped ZIF-8; (2) evaluating the enhancement of microwave thermal conversion efficiency <i>via</i> iron doping; (3) validating the nanoparticle's Fenton catalytic activity for reactive oxygen species (ROS) generation and glutathione depletion in the tumor microenvironment; and (4) demonstrating the synergistic antitumor efficacy of combined MWTT and CDT both <i>in vitro</i> and <i>in vivo</i>. Accordingly, Fe@Zif-8 was synthesized <i>via</i> a one-pot solvothermal method and systematically characterized. Its therapeutic performance was then rigorously assessed through a series of physicochemical and biological experiments. The iron dopants substantially enhance microwave absorption and dielectric loss effects in Zif-8 matrices, enabling Fe@Zif-8 to generate intensified hyperthermia under MW irradiation. Concurrently, iron ions released from the nanoplatform react with endogenous hydrogen peroxide (H₂O₂) <i>via</i> Fenton catalysis to produce substantial ROS. The concerted action of MWTT and CDT achieves rapid tumor ablation while significantly reducing therapeutic energy requirements. Furthermore, the platform served as an effective T2 contrast agent for magnetic resonance imaging (MRI), enabling non-invasive monitoring. This work provides a new approach for the preparation of nanomaterials with highly efficient anti-TNBC performance.