Fe-doped phase-transition nanodroplets for synergistic photothermal and starvation-enhanced ferroptosis in cancer therapy

Background: Ferroptosis therapy has emerged as a promising antitumor strategy by utilizing the Fenton reaction to destroy cancer cells, where Fe²⁺ catalyzes the decomposition of H₂O₂ into hydroxyl radicals (•OH). Despite the great potential of ferroptosis therapy in suppressing tumor growth, inadequate catalysts and reactants within tumors remains a major challenge before its clinical translation. Herein, we developed glucose oxidase (GOx)-loaded phase-transition nanodroplets (PND) modified with Fe-tannic acid (TA) networks (PND@GOx@Fe-TA) for enhanced antitumor efficacy of ferroptosis therapy via synergistic photothermal and starvation therapy. Results: PND@GOx@Fe-TA can convert glucose into H₂O₂, which not only provides sufficient H₂O₂ for Fenton reaction, but also consumes glucose to exert starvation therapy. In addition, the Fe-TA networks of PND@GOx@Fe-TA can be degraded upon reaching the tumor site, thus generating Fe²⁺ from Fe³⁺ via reduction by the overexpressed glutathione (GSH) in the tumor microenvironment. The Fe²⁺ then reacts with the in situ-generated H₂O₂ for enhanced Fenton reaction and induces ferroptosis of cancer cells. Additionally, the PND@GOx@Fe-TA exhibits photothermal effects under 808 nm laser irradiation, which not only accelerates the Fe²⁺-mediated Fenton reaction but also gasifies the liquid core of the PND, enabling its use as a contrast agent for contrast-enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI). Conclusions: In summary, the PND@GOx@Fe-TA represents a promising approach for multimodal imaging-guided antitumor therapy by synergistic starvation, photothermal and enhanced ferroptosis therapy.