CaCO3-assisted engineering of NIR-II phototheranostics enables photothermally enhanced ferroptosis in cancer through synergistically depleting intracellular glutathione.

Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a promising therapeutic target for cancer treatment. Strategies that disrupt intracellular antioxidant systems to induce ferroptosis in cancer cells have been extensively explored. Herein, we developed a pH-responsive phototheranostic agent (designated as FSB4Ca NPs) by encapsulating conjugated boron dipyrromethene tetramers (B4) within ferric ion-sulfasalazine metallo-network polymer-coated calcium carbonate hollow nanoparticles. Sulfasalazine, a known ferroptosis inducer that inhibits System Xc--mediated cysteine influx, synergizes with ferric ion-driven glutathione (GSH) depletion to collectively amplify intracellular lipid peroxidation. In addition to serving as a second near-infrared (NIR-II) fluorophore for tracking the in vivo distribution of FSB4Ca NPs, B4 mediates a photothermal effect that significantly enhances lipid peroxidation induction by boosting the Fenton catalytic activity of ferrous ions. Combined with localized 915-nm laser irradiation, intravenously administered FSB4Ca NPs achieved substantial tumor suppression in mouse models, with a complete remission rate of 80%. This study establishes a facile strategy for developing long-circulating NIR-II phototheranostic agents with self-amplified lipid peroxidation induction capacity, enabling photothermally augmented ferroptosis for cancer therapy.