Engineered Hf0.7Ti0.3O2 nanoparticles for efficient radiotherapy on rectal cancer via synergistically enhanced radiation deposition and ROS production

Preoperative radiotherapy is a cornerstone of treatment for locally advanced rectal cancer, but intrinsic tumor cell radio resistance remains a primary obstacle limiting therapeutic efficacy. Herein, for the first time, we successfully constructed Hf 0.7 Ti 0.3 O 2 @PEG (HT) nanoparticles by introducing titanium (Ti) into hafnium dioxide (HfO 2 ). These HT nanoparticles synergistically combined the superior X-ray energy deposition capability of Hf and the efficient radiation-induced ROS generation performance of Ti, leading to a 1.4-fold higher ROS yield compared to HfO 2 . Moreover, HT nanoparticles significantly enhanced radiosensitivity by inducing extensive DNA damage and oxidative stress in tumor cells. This resulted in a tumor inhibition rate of 87.7% ± 2.1% in mouse models. Notably, HT nanoparticles enabled a marked reduction in radiation dose while maintaining therapeutic efficacy and safety, overcoming the major limitation of conventional HfO 2 nanoradiosensitizers in ROS generation. This study presents a promising new approach for rectal cancer radiotherapy and holds significant potential for improving outcomes in radioresistant rectal cancer.