Orchestrating Chemo-Ferroptosis via Nonthermal Magnetocatalysis: A Cascade Amplification Paradigm for Breast Cancer Therapy.

Conventional tumor microenvironment-responsive nanotherapies are limited by their passive dependence on endogenous triggers, often resulting in suboptimal therapeutic efficacy due to tumor heterogeneity. Furthermore, monotherapy frequently induces drug resistance, highlighting the need for synergistic strategies targeting multiple cell death pathways. Here, we propose and experimentally validate a cascade amplification paradigm designed to overcome these intrinsic limitations by integrating a tumor microenvironment-priming stage with a remotely triggered external amplification stage. This paradigm is embodied in an alternating magnetic field-responsive iron-porphyrin metal-organic framework nanoplatform, termed DFT. Under acidic conditions, the DFT nanoplatform is primed, exhibiting a >3.5-fold accelerated corelease of doxorubicin and catalytic iron ions. Subsequent exposure to a low-intensity alternating magnetic field (10 mT, 40 kHz) operating in a strictly nonthermal regime serves as the external accelerator, markedly amplifying the Fenton-like catalytic process. This intensified oxidative burst synergistically coactivates ferroptosis and doxorubicin-induced apoptosis-2 mechanistically distinct pathways that collectively counteract drug resistance. In vivo validation demonstrated a 74.6% tumor growth inhibition-nearly a 2-fold enhancement compared with the passive DFT group (40.7%). Notably, this efficacy is achieved while remaining well within established clinical safety limits, thereby addressing the safety-efficacy trade-off inherent to conventional magnetic hyperthermia. Overall, this study establishes a robust and versatile paradigm that harnesses external physical fields not for thermal ablation, but as programmable tools to remotely regulate catalytic biochemistry. This nonthermal, field-driven strategy offers a promising and safer route to combating chemotherapy resistance.