Metal-phenolic networks with ferroptosis to deliver NIR-responsive CO for synergistic therapy

As an endogenous gasotransmitter, CO has achieved tremendous advances in cancer treatment through selectively killing cancer cells. However, the application of CO in tumor immunotherapy has not been reported and the tumor targeting delivery is still a tremendous challenge. Herein, thermosensitive boronic acid group-containing CO prodrug was synthesized and fabricated with tannic acid (TA) and iron (Fe) to form metal-phenolic networks, and then loaded with near-infrared (NIR) photothermal agent IR820 to form FeCO-IR820@Fe^IIITA for combinational therapy of CO and photothermal therapy. Ferroptosis can also be enhanced due to the Fe³⁺ incorporation. After TA reduced Fe³⁺ into Fe²⁺, Fe²⁺ might lead to intracellular Fenton reaction. Furthermore, in combination with CTLA-4 blockade immunotherapy, FeCO-IR820@Fe^IIITA remarkably inhibited breast tumor growth, suppressed the lung metastasis and improved the antitumor immune response. To summarize, FeCO-IR820@Fe^IIITA provides a potential novel option for CO/photothermal/immune synergistic therapy with enhanced ferroptosis through simple compositions and facile synthesis process.