X-ray radiotherapy is a common method of treating cancerous tumors or other malignant lesions. The side effects of this treatment, however, can be deleterious to patient quality of life if critical tissues are affected. To potentially lower the effective doses of radiation and negative side-effects, new classes of nanoparticles are being developed to enhance reactive oxygen species production during irradiation. This report presents the synthesis and radiotherapeutic efficacy evaluation of a new nanoparticle formulation designed for this purpose, composed of a CaF2 core, mesoporous silica shell, and polyethylene glycol coating. The construct was additionally doped with Tb and Eu during the CaF2 core synthesis to prepare nanoparticles (NPs) with X-ray luminescent properties for potential application in fluorescence imaging. The mesoporous silica shell was added to provide the opportunity for small molecule loading, and the polyethylene glycol coating was added to impart aqueous solubility and biocompatibility. The potential of these nanomaterials to act as radiosensitizers for enhancing X-ray radiotherapy was supported by reactive oxygen species generation assays. Further, in vitro experiments indicate biocompatibility and enhanced cellular damage during X-ray radiotherapy.