Cleavage of Homonuclear Chalcogen‐Chalcogen Bonds in a Hybrid Platform in Response to X‐Ray Radiation Potentiates Tumor Radiochemotherapy

Abstract Chalcogens are used as sensitive redox‐responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than by internal environmental stimuli, enable site‐directed and real‐time drug degradation in target lesions. This approach helps to bypass chemoresistance and global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated a hybrid monodisperse organosilica nanoprodrug based on homonuclear single bonds (disulfide bonds (S−S, approximately 240 kJ/mol), diselenium bonds (Se−Se, approximately 172 kJ/mol), and tellurium bonds (Te−Te, 126 kJ/mol)), including ditelluride‐bond‐bridged MONs (DTeMSNs), diselenide‐bond‐bridged MONs (DSeMSNs) and disulfide‐bond‐bridged MONs (DSMSNs). The results demonstrated that differences in electronegativities and atomic radii influenced their oxidation sensitivities and reactivities. Tellurium, with the lowest electronegativity, showed the highest sensitivity, followed by selenium and sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure to X‐rays, resulting in oxidation to TeO 3 2− . Furthermore, chalcogen‐hybridized organosilica was loaded with manganese ions (Mn 2+ ) to enhance the release of Mn 2+ during radiotherapy, thereby activating the the stimulator of interferon genes (STING) pathway and enhancing the tumor immune response to inhibit tumor growth. This investigation of hybrid organosilica deepens our understanding of chalcogens response characteristics to radiotherapy and enriches the design principles for nanomedicine based on prodrugs.