AbstractIn cancer radiation therapy, dose enhancement by nanoparticles has to date been investigated only for external beam radiotherapy (EBRT). Here, we report on an in silico study of nanoparticle-enhanced radiation damage in the context of internal radionuclide therapy. We demonstrate the proof-of-principle that clinically relevant radiotherapeutic isotopes (i.e. ²¹³Bi, ²²³Ra, ⁹⁰Y, ¹⁷⁷Lu, ⁶⁷Cu, ⁶⁴Cu and ⁸⁹Zr) labeled to clinically relevant superparamagnetic iron oxide nanoparticles results in enhanced radiation damage effects localized to sub-micron scales. We find that radiation dose can be enhanced by up to 20%, vastly outperforming nanoparticle dose enhancement in conventional EBRT. Our results demonstrate that in addition to the favorable spectral characteristics of the isotopes and their proximity to the nanoparticles, clustering of the nanoparticles results in a nonlinear collective effect that amplifies nanoscale radiation damage effects by electron-mediated inter-nanoparticle interactions. In this way, optimal radio-enhancement is achieved when the inter-nanoparticle distance is less than the mean range of the secondary electrons. For the radioisotopes studied here, this corresponds to inter-nanoparticle distances <50 nm, with the strongest effects within 20 nm. The results of this study suggest that radiolabeled nanoparticles offer a novel and potentially highly effective platform for developing next-generation theranostic strategies for cancer medicine.