Nanoscintillator‐Mediated X‐Ray‐Triggered Boosting Transformation of Fe³⁺ into Fe²⁺ for Enhancing Tumor Ferroptosis/Immunotherapy

Abstract Ferroptosis therapy induced by iron‐catalyzed Fenton reaction has offered enormous opportunities for tumor therapy. Unfortunately, high catalytic activity ferrous (Fe²⁺)‐based therapeutic agent has remained challenging due to the instability of Fe²⁺. Herein, an X‐ray‐activated Fe²⁺ supply platform, termed “PFCN”, containing the core of CaWO₄ nanoscintillator to emit ultraviolet (UV) light and Fe₃O₄ decorated on the surface to deliver excessive Fe²⁺ is proposed. Under X‐ray excitation, the UV light emitted by CaWO₄ can catalyze ferric (Fe³⁺) to generate Fe²⁺, which further cascades the Fenton reaction to induce highly toxic hydroxyl radicals generation. More importantly, immunogenic cell death‐associated immunotherapy is simultaneously triggered during this process. Experiments conducted in vitro and in vivo revealed that X‐ray‐triggered PFCN shows superior tumor therapeutic efficacy, contributing i) enhanced radiotherapy; ii) X‐ray‐activated ferroptosis therapy; and iii) ferroptosis/radiotherapy‐induced immunotherapy. Besides, PFCN can be utilized as an MR/CT dual‐mode imaging contrast agent for tumor diagnosis and treatment monitoring. The study provides a novel example of an X‐ray‐activated ferrous‐regeneration platform for imaging‐guided augmenting tumor ferroptosis/immunotherapy