Double-Responsive Metallic Magnetic Nanoparticles Based on Tumor Microenvironment “Leverage” Rebalancing for Triple Collaborative Cancer Therapy

Targeted perturbation of redox balance through concurrent elevation of reactive oxygen species (ROS) production and glutathione (GSH) depletion has emerged as a therapeutic paradigm for triggering tumor cell apoptosis. Nevertheless, the conventional single-agent system demonstrates limited therapeutic efficacy due to insufficient oxidative stress amplification within tumor cells. Herein, we designed pH- and GSH double-responsive metallic magnetic Ag-NH2–CoFe2O4@C@DOX nanoparticles (ANFCD NPs), which disrupted the redox balance within the tumor microenvironment (TME) to achieve synergistic chemodynamic therapy (CDT), photothermal therapy (PTT), and chemotherapy (CT) effects. In the acidic TME, ANFCD NPs functioned as both a Fenton catalyst and GSH depletor through the reversible redox property of Fe (II/III) and Co (I/II), inducing oxidative stress and exerting a "leverage" rebalancing to potentiate CDT. Additionally, ANFCD NPs showed high photothermal conversion efficiency, enhancing PTT efficacy via magnetic targeting-driven tumor accumulation. Meanwhile, they could also responsively release DOX to achieve CT. More importantly, the hyperthermia generated by ANFCD NPs not only effectively eradicated tumor cells but also boosted the CDT effect and promoted DOX release, ultimately achieving the aim of combined therapy. Therefore, such a nanomaterial is a promising therapeutic agent for disrupting redox homeostasis to augment multimodal collaborative therapy, which might show further applications in nanomedical science.