Energy-Transducing Scintillating Nanoparticles for Combined Proton Beam Therapy and Photodynamic Therapy

Abstract Deep-seated tumors in complex anatomical regions pose significant challenges for conventional photodynamic therapy (PDT) due to limited light penetration. While proton beam therapy (PBT) offers superior spatial precision via the Bragg peak, its biological effectiveness is comparable to X-ray therapy, necessitating potent radiosensitizers to overcome radioresistant tumors. Herein, we report the design of NaLuF4:Ce,Tb@NaYF4 scintillating nanoparticles (ScNPs) as a robust platform for an integrated PBT-PDT. By leveraging the high-atomic-number element lutetium (Lu), these ScNPs facilitate enhanced radiation deposition and serve as efficient energy transducers with multimodal responsiveness to ultraviolet (UV), X-ray, and clinical proton beams. Upon proton irradiation, the ScNPs exhibit proton-induced luminescence to activate the photosensitizer Rose Bengal (RB), enabling deep-tissue reactive oxygen species (ROS) generation and bypassing the penetration constraints of external light sources. Furthermore, the persistent luminescence lifetime is flexibly tailored by modulating the Ce3+ doping concentration, ensuring controllable therapeutic action. In vitro and in vivo studies confirm that this synergistic approach significantly intensifies tumor DNA double-strand breaks and triggers a robust apoptotic cascade, far surpassing the efficacy of PBT or PDT monotherapies. This study marks the novel development of proton-beam-induced luminescent ScNPs for combined PBT-PDT, establishing a high-precision methodological framework that optimizes spatiotemporal control for next-generation oncological interventions.