Recently, photodynamic therapy (PDT) has attracted considerable attention as a less invasive method for cancer treatment involving the use of ultraviolet–visible (UV–Vis) light, near-infrared (NIR) light, or X-ray (XR) to activate photosensitizers (PSs) and kill tumor cells. However, the penetration depths of UV–Vis and NIR are not sufficient to reach tumors located in the internal organs. Using XR as a light source requires high doses of protoporphyrin IX (PpIX) and XR irradiation. Therefore, we developed a novel strategy involving the use of low-dose XR, therapeutic ultrasound (US) and a newly proposed nanovehicle (SiO2 nanospheres conjugated with PpIX and then decorated with Au nanoparticles; PpIX-loaded Au@SNs). This vehicle was designed for enhancing targeted sonosensitization (i.e., US-induced PpIX sensitization) and exerting a radiation dose enhancement effect. The targeted sonosensitization was enhanced through the PpIX–SiO2 conjugation (which reduces self-quenching of PpIX) and PpIX–mitochondrial colocalization. This synergistically working with the radiation dose enhancement effect of Au and Si might significantly enhance the efficacy of subsequent XR irradiation. Results showed that PpIX-loaded Au@SNs-internalized tumor cells were effectively killed after the sequential administration of US and XR. Importantly, the doses of XR and PpIX are significantly lower than those described in the literature.
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