X-ray Radioenhancement by Hafnium(IV) Oxide Nanocrystals of Varying Sizes and Shapes

Nanoparticle (NP)-mediated radiosensitization holds great promise to improve radiotherapy outcomes. While HfO 2 -based agents such as NBTXR3 have advanced into clinical stages, the role of particle morphology at the sub-10 nm scale remains largely unexplored. Here, we engineered three hafnium(IV) oxide nanocrystals (HfO 2 NCs) with different shapes and sizes and systematically evaluated their biological performance in MCF-7 breast cancer cells. Spherical NCs showed higher cellular internalization and significantly increased acellular reactive oxygen species (ROS) generation under X-ray exposure, with the dose-enhancement factor in terms of ROS (DEF ROS ) reaching 6.02 at 6 Gy. Clonogenic assays confirmed stronger radiosensitization by spherical particles, with the survival fraction at 2 Gy (SF 2 ) reduced to 0.36 and the dose-modifying ratio at 50% survival (DMR 50 ) increased to 1.32, compared to the less effective anisotropic ellipsoidal counterparts. These findings establish size- and shape-dependent biological behavior as a critical parameter for optimizing nanoscale radioenhancers. Moreover, spherical ultrasmall HfO 2 –S NCs were identified as highly effective radiosensitizers, offering a rational design strategy for next-generation nanomaterials in clinical radiotherapy.