Multimodal radiosensitization by hafnium oxide nanoparticles and HDAC inhibitors: mechanistic insights

Radiation therapy is routinely utilized in cancer treatment, often in combination with chemotherapy, but is limited by collateral damage to healthy tissues and radioresistance of some tumors. Radiosensitizing agents can enhance tumor cell susceptibility to ionizing radiation, allowing effective treatment at lower doses. High-atomic-number metal-based nanoparticles, such as hafnium oxide (HfO₂NP), can locally amplify the impact of ionizing radiation on cancer cells, augment the radiation-triggered generation of reactive electrons and oxygen species (ROS), induce DNA damage, and ultimately lead to cell death. We hypothesized that this effect can be further enhanced by histone deacetylase (HDAC) inhibitors, which maintain the chromatin in a relaxed state and render the DNA more accessible to genotoxic stress. In this study, we found that HfO₂NPs and the HDAC inhibitor, when combined with irradiation, induced significantly higher ROS production, massively reduced mitochondrial membrane potential, and increased DNA double-strand break formation in cancer cells compared to untreated or single-agent-treated cells. These effects led to a marked reduction in colony-forming potential in both 2D and 3D models and induced significant apoptosis. No cytotoxicity was observed in non-cancerous fibroblasts. HfO₂NPs and the tested HDAC inhibitor form a remarkably efficient cancer-selective radiosensitizing combination, where the enzyme inhibitor facilitates the irradiation-induced DNA-damaging potential of the nanoparticles. This outstanding multimodal approach can target radioresistant cancer cells, while not affecting healthy cells, underscoring its potential in a next-generation nanomedicine-based radiosensitizing strategy to attenuate cancer cell growth for an improved therapeutic outcome.