Ischemic stroke is the leading cause of adult disability in the United States and the second leading cause of death worldwide.[1] Reactive oxygen species (ROS), such as the superoxide anion (O2CÀ), hydrogen peroxide (H2O2), and hydroxyl radical (HOCÀ), are generated and accumulate during ischemic periods. These species induce oxidative damage, which is one of the most critical mechanisms responsible for causing ischemic injury,[2] and oxidative damage elicits stroke-related cell death mechanisms, such as apoptosis.[3] As a result, neuronal networks and neurovascular units are completely destroyed, and the brain function is stopped. However, no effective neuroprotective therapy for ischemic stroke has been developed for clinical practice. Despite the availability of antioxidant drugs, no treatments have been proven to protect against oxidative damage after acute ischemic stroke in humans.

Ceria nanoparticles are known to exhibit free radical scavenging activity by reversibly binding oxygen and shifting between the Ce3+(reduced) and Ce4+(oxidized) forms at the particle surface.[4] From the crystal structure of ceria nanoparticles, cerium ions mostly exist in the valence state of Ce4+; however, reduction in particle size results in oxygen vacancies from the particle surface, which allows the coexistence of Ce3+.[5] Moreover, the catalytic properties of ceria nanoparticles can be further enhanced by using ultrasmall nanoparticles of less than 4 nm.[6] The ability of ceria nanoparticles to switch between oxidation states and scavenge free radicals is comparable to biological antioxidants. In fact, it was