A triple-cascade nanoreactor for potent anti-tumor chemodynamic and immunotherapy

Chemodynamic therapy (CDT) has shown promising effects in the treatment of malignant tumors, especially in inducing immunogenic cell death (ICD). However, the therapeutic efficacy of CDT is much weakened due to limitations in tumor oxidative stress response, and intracellular H₂O₂ and catalyst levels. In order to solve these challenges, we have designed an intracellular acid-activated cascade nanoreactor (Sal/Fe₃O₄@SiO₂-NaCN) which induces ICD by accelerating the process of CDT-mediated ferroptosis. The nanoreactor operates in three synergistic steps. Firstly, the platform can catalyze the degradation of glucose to gluconic acid and H₂O₂ under ultrasound (US) exposure in an acidic environment. Secondly, Fe₃O₄ can then convert this H₂O₂ to ·OH. In addition, salinomycin (Sal) causes Fe accumulation in the cell and enhances the efficacy of the Fenton process. Extensive in vitro and in vivo experiments reveal the production of reactive oxygen species, accumulation of Fe in cells, and stimulation of ferroptosis and ICD. In a bilateral tumor model, magnetic resonance signals and excellent therapeutic effects were observed in vivo. This novel nanoreactor offers a promising strategy for CDT-based cancer treatment and immunotherapy.