Stimuli-Responsive Small-on-Large Nanoradiosensitizer for Enhanced Tumor Penetration and Radiotherapy Sensitization

Development of an efficient nanoradiosensitization system that enhances the radiation doses in cancer cells to sensitize radiotherapy (RT) while sparing normal tissues is highly desirable. Here, we construct a tumor microenvironment (TME)-responsive disassembled small-on-large molybdenum disulfide/hafnium dioxide (MoS₂/HfO₂) dextran (M/H-D) nanoradiosensitizer. The M/H-D can degrade and release the HfO₂ nanoparticles (NPs) in TME to enhance tumor penetration of the HfO₂ NPs upon near-infrared (NIR) exposure, which can solve the bottleneck of insufficient internalization of the HfO₂ NPs. Simultaneously, the NIR photothermal therapy increased peroxidase-like catalytic efficiency of the M/H-D nanoradiosensitizer in TME, which selectively catalyzed intratumorally overexpressed H₂O₂ into highly oxidized hydroxyl radicals (·OH). The heat induced by PTT also relieved the intratumoral hypoxia to sensitize RT. Consequently, this TME-responsive precise nanoradiosensitization achieved improved irradiation effectiveness, potent oxygenation in tumor, and efficient suppression to tumor, which can be real-time monitored by computed tomography and photoacoustic imaging.