Gold Nanoparticle-Mediated DNA Damage Under FLASH Electron-Beam Irradiation: A Monte Carlo Study

FLASH radiotherapy, which delivers radiation at ultrahigh dose rates (UHDRs) exceeding 40 Gy/s, has attracted considerable attention because of its potential to spare normal tissues while maintaining tumour control. Gold nanoparticles (GNPs) are promising radiosensitizers that enhance radiation-induced biological effects through increased production of reactive oxygen species (ROS) and subsequent DNA damage. However, the influence of GNPs on DNA damage under FLASH irradiation remains poorly understood. In this study, Geant4-DNA Monte Carlo simulations were performed to investigate the effects of GNP size and dose rate on DNA damage during UHDR electron-beam irradiation. DNA damage was quantified through both direct and indirect mechanisms based on energy deposition in DNA backbone segments and interactions between radiation-induced radical species and DNA, and was evaluated relative to equivalent water nanoparticle (WNP) controls. The results demonstrated a dose rate-dependent reduction in both relative single-strand breaks (RSSBs) and relative double-strand breaks (RDSBs) arising from direct and indirect DNA damage mechanisms. For the 10 keV monoenergetic model condition, the 10 nm GNP produced the greatest radiosensitization among the particle sizes investigated, with the matched GNP/WNP analysis showing a maximum 5-fold enhancement in direct SSB yields. In contrast, substantially weaker GNP-specific enhancement and no comparable size-dependent effect were observed at 1 MeV. These findings demonstrate that GNP-mediated radiosensitization depends on both nanoparticle size and electron energy under the irradiation conditions investigated. The greater enhancement observed for the 10 nm GNP at 10 keV should therefore not be interpreted as identifying a universally optimal GNP size for FLASH radiotherapy.