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

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