Abstract
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 (131I@CaO2), fabricated through biomimetic mineralization followed by chloramine-T mediated 131I-radiolabeling, for high-efficiency internal-radioimmunotherapy. 131I@CaO2 effectively enhances the internalization of 131I to improve internal-radiotherapy and exhibits pH-responsive biodegradability, remaining stable under physiological condition while progressively degrading in tumor microenvironment to release H2O2, O2 and Ca2+. These bioactivators synergistically enhance 131I-induced internal-radioimmunotherapy through both radiosensitization and immune activation: H2O2 and O2 boost 131I-induced ROS generation while Ca2+ disrupted mitochondrial respiration to reduce oxygen consumption and ATP production (suppressing Ca2+ pump activity), creating a positive feedback loop of oxygen supply and ion overload, thereby achieving radiosensitization; Concurrently, O2 alleviates tumor hypoxia to downregulate PD-L1 expression and Ca2+ overload activates dual pyroptosis pathways, establishing a robust immunogenic microenvironment. As a result, 131I@CaO2 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.