Irradiation of tumors laden with gold nanoparticle (NP) results in radiation dose enhancement via increased secondary electron showers emanating from particleradiation interactions. However, it is challenging to load tumors non-invasively with adequate gold to realize the true potential for radiosensitization. In preliminary data we demonstrate that thermosensitive liposomes (TSLs) laden with gold NPs accumulate within cancers via their leaky vasculature. Mild hyperthermia (42οC) induced by FUS leads to rupture of liposomes and deployment of the gold payload deep within tumors. Subsequent radiation results in significant delay in tumor regrowth (radiosensitization). We hypothesize that this is mediated by deep-penetrating gold NPs and the radiation dose enhancement by secondary photo- and Auger- electrons. In preliminary data, we demonstrate successful fabrication of TSLs with gold NPs, their release kinetics upon heating, hyperthermia generation in vivo using FUS, and radiosensitization via triggered release of gold NPs. To test the hypothesis that this is mediated by deep-penetrating gold NPs, we propose in vivo biodistribution experiments using scanning electron microscopy and inductively-coupled plasma mass spectrometry of tumor core vs. periphery in mice treated with gold-ladern TSLs with and without FUS-hyperthermia. We also propose more detailed in vivo experiments using non-thermosensitive liposomes as control. Lastly, we define optimal parameters for maximal delivery of deep-penetrating gold NPs within tumors and synergy when this is coupled with clinically relevant fractionated radiotherapy regimens. Once completed, these studies will provide the framework for development of a readily deployable class solution for radiosensitization of multiple tumor types using TSLs laden with gold.