Aim: Radiotherapy is an important treatment modality against breast and thoracic cancer, bringing significant improvement in tumor control and survival. Nevertheless, it also results in variable degrees of cardiac exposure to ionizing radiation. Resultant radiation-induced heart disease (RIHD) typically manifests at protracted post-irradiation times and can involve a wide range of underlying pathologies including heart failure. Past work from our group has identified an intervention involving systemic administration of human embryonic stem cell (hESC)-derived extracellular vesicles (EV) shown to resolve radiation-induced lung disease (RILD). However, potential treatment-associated complications to the heart were not investigated. Using a similar EV-based treatment paradigm, we conducted a safety to study to evaluate the potential impact of systemically administered EV on cardiac functionality after a single image guided dose (14 Gy) of thoracic irradiation. Method: Separate cohorts of control (CONT: n=8, no irradiation, no EV), irradiated (IR: n=8, 14 Gy + 4 weekly vehicle injections) and irradiated and EV treated (IR + EV: n=8, 14 Gy + 4 weekly EV injections) mice were implemented in this study. For the irradiated groups, mice were given 4 systemic (retroorbital) vehicle injections +/- EV the week of and for 3 weeks after IR. Echocardiography follow-up was used to measure E/A ratio, ejection fraction (EF), shortening fraction (SF), left ventricular mass (LV mass) and end diastolic volume (EDV) 20-weeks following IR.Results: Radiation exposure caused a significant drop in E/A ratios compared with mice that did not receive radiation, with non-significant changes in other key indicators of cardiac function. EV treatments were not found to have an observable effect on the E/A ratio or any other indices of cardiac function among the different cohorts. Conclusions: Irradiated mice had lower E/A ratios, but other indicators of cardiac function were unchanged, suggesting that thoracic exposures compromised diastolic function without impacting EF. Diastolic dysfunction was most likely linked to increased radiation-induced fibrosis and myocardium stiffness. Importantly, EV treatments were not observed to adversely impact cardiac function, pointing to the safety of this potential intervention for RILD.