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Iron oxide nanoparticles (IONPs) are chemically inert materials and have been mainly used for imaging applications and drug deliveries. However, the possibility whether they can be used as therapeutic drugs themselves has not yet been explored. We reported here that Fe₂O₃ nanoparticles (NPs) can protect hearts from ischemic damage at the animal, tissue and cell level. The cardioprotective activity of Fe₂O₃ NPs requires the integrity of nanoparticles and is not dependent upon their surface charges and molecules that were integrated into nanoparticles. Also, Fe₂O₃ NPs showed no significant toxicity towards normal cardiomyocytes, indicative of their potential to treat cardiovascular diseases.