Radionuclide-labeled oxygen-self-supplying calcium reservoir for high-efficiency radioimmunotherapy via synergistic pyroptosis activation and PD-L1 downregulation

Internal radiation therapy is an irreplaceable modality for local tumor treatment, offering high-effective radiotherapy while sparing surrounding healthy tissues. However, current clinical non-biodegradable radionuclide implants suffer from permanent retention risks and limited efficacy against distal tumors due to inadequate immune activation. Herein, we engineered a biodegradable radionuclide-labeled oxygen-self-supplying calcium reservoir ( 131 I@CaO 2 ), fabricated through biomimetic mineralization followed by chloramine-T mediated 131 I-radiolabeling, for high-efficiency internal-radioimmunotherapy. 131 I@CaO 2 effectively enhances the internalization of 131 I to improve internal-radiotherapy and exhibits pH-responsive biodegradability, remaining stable under physiological condition while progressively degrading in tumor microenvironment to release H 2 O 2 , O 2 and Ca 2+ . These bioactivators synergistically enhance 131 I-induced internal-radioimmunotherapy through both radiosensitization and immune activation: H 2 O 2 and O 2 boost 131 I-induced ROS generation while Ca 2+ disrupted mitochondrial respiration to reduce oxygen consumption and ATP production (suppressing Ca 2+ pump activity), creating a positive feedback loop of oxygen supply and ion overload, thereby achieving radiosensitization; Concurrently, O 2 alleviates tumor hypoxia to downregulate PD-L1 expression and Ca 2+ overload activates dual pyroptosis pathways, establishing a robust immunogenic microenvironment. As a result, 131 I@CaO 2 effectively eliminates both primary and distant tumors by activating immune cells. This study simultaneously resolves the long-term retention risks of non-biodegradable radionuclide and the dichotomy between local radiotherapy and comprehensive immune modulation.