A tandem-unlocked cascade nanoreactor for high-contrast magnetic resonance imaging-guided enhanced ferroptosis-chemo synergistic therapy

Ferroptosis holds significant promise in cancer therapy due to its unique form of programmed cell death, marked by a strong ability to selectively target drug-resistant cells. However, therapeutic approaches leveraging ferroptosis face challenges associated with restricted efficacy, specificity, and unreliable imaging techniques for monitoring treatment progression. Herein, we design a sequential tandem-unlocked cascade nanoreactor (TPZ/HMOS/IO@GOx) for MRI-guided enhanced ferroptosis-chemo synergistic therapy. Specifically, within the tumor TME, GSH triggers the degradation of HMOS, leading to the release of GOx, IO, and TPZ from TPZ/HMOS/IO@GOx. The liberated GOx catalyzes the conversion of endogenous glucose, consuming O₂ to generate H₂O₂ and gluconic acid. The resultant increase in acidity accelerates the decomposition of IO into Fe²⁺/Fe³⁺. Subsequently, the Fenton reaction between Fe²⁺ and accumulated H₂O₂ generates ROS and Fe³⁺, while the reaction between Fe³⁺ and H₂O₂ produces ROS and Fe²⁺, establishing a cyclic catalytic effect. Fe³⁺ interacts with GSH to yield Fe²⁺ and GSSG, thereby intensifying oxidative stress on tumor cells. As hypoxia worsens, TPZ is activated to generate toxic radical species, further enhancing the cytotoxic effect on tumor cells and synergizing with ferroptosis treatment. The orchestrated sequence of TME-activated cascading reactions, initiated by TPZ/HMOS/IO@GOx (<i>i.e.</i>, tandem-unlocked cascade nanoreactor), demonstrates exceptional antitumor efficacy both <i>in vitro</i> and <i>in vivo</i>. Moreover, the TME-triggered release of IO from TPZ/HMOS/IO@GOx enables high-contrast "ON" <i>T</i> ₁-weighted MRI in tumor-bearing mice, providing precise guidance for the <i>in vivo</i> distribution of nanomedicine and tumor ferroptosis therapy.