A Dual-Pronged Hafnia–Prodrug–Lipid Nanoplatform Coupling Radiosensitization and DNA Homologous Recombination Inhibition

Emerging nanomedicine strategies have established clinical translation and the ability to offset conventional therapeutic challenges. This study aimed to report the development and analysis of a nanoscale material that functioned as both a high-Z radiosensitizer and a prodrug delivery system. In this study, a nanoscale platform using two complementary radiosensitizing mechanisms was designed and developed to overcome nonspecific toxicity, which is a challenge in both chemotherapy and radiotherapy. High-Z physical radiosensitization was coupled with the inhibition of a critical DNA double-strand break repair mechanism, homologous recombination, through a lipid nanoparticle decorated with ultrasmall Hafnia nanoparticles and loaded with an amphiphilic prodrug. In vitro and in vivo studies demonstrated significant enhancement of therapeutic effects, cell killing, or tumor regression, respectively, versus radiation alone. These results support the use of this combination system as a practical strategy for maintaining treatment efficacy at modest doses of radiation and offset associated adverse effects.