Engineering Atomic Ag1−N2 Sites with Enhanced In Situ Cherenkov Radiation-Induced Photodynamic Therapy and Radionuclide Therapy in Differentiated Thyroid Cancer

Abstract Combination of 131I radioiodine therapy and photodynamic therapy represents a potential strategy for improving the treatment of differentiated thyroid cancer. Herein, we developed a silver single-atom carbon nitride photosensitizer (Ag1−N2), which is activated by the in situ light source of 131I Cherenkov radiation, for effective photodynamic therapy in differentiated thyroid cancer. Atomically dispersed Ag formed well-defined Ag−N2 coordination sites on g-C3N4, which adjust the energy band structure, optimizes *OH desorption, and inhibits its excessive reduction, thereby promoting the one-electron reduction of H2O2 into •OH and cascading reactive oxygen species amplification. Additionally, Ag1−N2 showed preliminary tolerability. In combination with Na131I, Ag1−N2 enhanced intracellular ROS generation, reduced TPC-1 cell viability by approximately 80%, and produced greater tumor-growth inhibition than either monotherapy. This study presents an in situ Cherenkov-activated silver single-atom nanoplatform that offers a promising combination-therapy strategy for differentiated thyroid cancer.