Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology. Over the years, PDT techniques have been developed for the treatment of deep-seated cancers. However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment. We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (Y₂O₃:Eu@SiO₂) with an annealing process. Our results revealed that annealed Y₂O₃:Eu@SiO₂ could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules. The crystallinity of Y₂O₃:Eu@SiO₂ was demonstrated to enable the generation of electron-hole (e^--h⁺) pairs in Y₂O₃ under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen. In particular, combining Y₂O₃:Eu@SiO₂ with fractionated radiation therapy increased radio-resistant tumor cell damage. Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (_SO₂) and reoxygenation of the hypoxia region. The results of this study support applicability of the integration of fractionated radiation therapy with Y₂O₃:Eu@SiO₂, achieving synchronously in-depth and oxygen-insensitive X-ray PDT. Furthermore, we demonstrate Y₂O₃:Eu@SiO₂ exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the Y₂O₃:Eu@SiO₂ concentration in vivo. With the pronounced X-RL for in-vivo imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.

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