Abstract

Elevated intracellular glutathione, intratumoral hypoxia, and excessive polyamines severely compromise the efficacy of radiotherapy (RT) by attenuating radiation damage and maintaining an immunosuppressive tumor microenvironment (ITME). Strategies that concurrently address these obstacles are urgently needed to enhance RT outcomes. Herein, we fabricated a biomimetic nanoplatform (PCuP) via the self-assembly of copper ions and piceatannol into CuP nanometal-polyphenol cores, followed by surface camouflage with platelet membranes (PM). Owing to the platelet membrane coating, PCuP preferentially accumulates in tumor tissues with disrupted vasculature. At the tumor site, PCuP catalyzes hydrogen peroxide to produce oxygen, relieving hypoxia and sensitizing the tumors to RT. Simultaneously, it generates reactive oxygen species (ROS) that cooperate with RT to induce immunogenic cell death (ICD). Furthermore, PCuP inhibits arginase 2 (Arg2) to deplete polyamines, suppressing tumor DNA repair and remodeling the ITME. In vivo experiments using oral squamous cell carcinoma (OSCC) models demonstrated that PCuP promotes dendritic cell maturation, activates systemic antitumor immunity, and drastically reduces post-RT tumor recurrence. This study presents the first nanoplatform integrating polyamine depletion with radioimmunotherapy, offering a promising strategy to design advanced radiosensitizers for improving RT efficacy and lowering tumor recurrence.