X-ray-triggered intratumoral photosynthesis for oxygenation-enhanced ferroptosis and radiosensitization

Radiotherapy (RT), a cornerstone treatment, is fundamentally limited by tumor hypoxia-induced radioresistance and the associated need for high doses that cause severe toxicities. Herein, we developed an innovative bionanohybrid platform (Cyan@ZWP), by integrating X-ray-activated afterglow nanoparticles within oxygenic cyanobacteria. This system is designed to overcome the penetration-depth barrier of external light and achieve sustained intratumoral oxygen production for RT potentiation. Upon X-ray irradiation, the afterglow nanoparticles emit persistent visible light internally, which drives continuous photosynthetic oxygen evolution by the cyanobacteria, thereby sustainably alleviating tumor hypoxia and sensitizing tumors to radiation. Concurrently, X-ray irradiation induces substantial reactive oxygen species generation, causing severe DNA strand damage. The generated oxygen not only fixes X-ray-induced DNA damage but also acts synergistically with radiation to amplify lipid peroxidation, activating ferroptosis, which is confirmed by Western blot analysis of key markers and immunofluorescence staining in tumor tissues. This dual mechanism of combining enhanced DNA damage fixation and potentiated ferroptosis, collectively results in significant tumor suppression both in vitro and in vivo. Overall, this biohybrid strategy provides a novel approach to overcoming microenvironmental limitations in RT and establishes a foundation for potential clinical translation.