Integrating multifunctional nanostructures capable of radiotherapy and photothermal ablation is an emerging alternative in killing cancer cells. In this work, we report a novel plasmonic heterostructure formed by decorating AuPt nanoparticles (NPs) onto the surfaces of CuS nanosheets (AuPt@CuS NSs) as a highly effective nanotheranostic toward dual-modal photoacoustic/computed tomography imaging and enhanced synergistic radiophotothermal therapy. These heterostructures can confer higher photothermal conversion efficiency via the local electromagnetic enhancement as well as a greater radiation dose deposition in the form of glutathione depletion and reactive oxygen species generation. As a result, the depth of tissue penetration is improved, and hypoxia of the tumor microenvironment is alleviated. With synergistic enhancement in the efficacy of photothermal ablation and radiotherapy, the tumor can be eliminated without later recurrence. It is believed that these multifunctional heterostructures will play a vital role in future oncotherapy with the enhanced synergistic effects of radiotherapy and photothermal ablation under the guided imaging of a potential dual-modality system.

Radiosensitizers are agents capable of amplifying injury to tumor tissues by enhancing DNA damage and fortifying production of radical oxygen species (ROS). The use of such radiosensitizers in the clinic, however, remains limited by an insufficient ability to differentiate between cancer and normal cells and by the presence of a reversible glutathione system that can diminish the amount of ROS generated. Here, to address these limitations, we design an H2O2-responsive prodrug which can be premixed with lauric acid (melting point ∼43 °C) and loaded around the surface of silica-coated bismuth nanoparticles (BSNPs) for cancer-specific photoradiotherapy. Particularly, silica coating confers BSNPs with improved chemical stability against both near-infrared light and X-rays. Upon photothermal heating, lauric acid is melted to trigger prodrug release, followed by its transformation into p-quinone methide via H2O2 stimulation to irreversibly alkylate glutathione. Concurrently, this heat boosts tumor oxygenation and helps relieve the hypoxic microenvironment. Following sequential irradiation by X-rays, BSNPs generate plentiful ROS, which act in combination with these events to synergistically induce cell death via DNA breakage and mitochondria-mediated apoptosis pathways, ultimately enabling effective inhibition of tumor growth in vivo with high tumor specificity and reduced side effects. Collectively, this work presents a promising approach for the improvement of other ROS-responsive proalkylating agents, while simultaneously highlighting a robust nanosystem for combining these prodrugs with photoradiosensitizers to realize precision photoradiotherapy.