Xenon Nanobubbles for the Image-Guided Preemptive Treatment of Acute Ischemic Stroke via Neuroprotection and Microcirculatory Restoration

Early lesion site diagnosis and neuroprotection are crucial to the theranostics of acute ischemic stroke. Xenon (Xe), as a nontoxic gaseous neuroprotectant, holds great promise for ischemic stroke therapy. In this study, Xe-encapsulated lipid nanobubbles (Xe-NBs) have been prepared for the real-time ultrasound image-guided preemptive treatment of the early stroke. The lipids are self-assembled at the interface of free Xe bubbles, and the mean diameter of Xe-NBs is 225 ± 11 nm with a Xe content of 73 ± 2 μL/mL. The in vitro results show that Xe-NBs can protect oxygen/glucose-deprived PC12 cells against apoptosis and oxidative stress. Based on the ischemic stroke mice model, the biodistribution, timely ultrasound imaging, and the therapeutic effects of Xe-NBs for stroke lesions were investigated in vivo. The accumulation of Xe-NBs to the ischemic lesion endows ultrasound contrast imaging with the lesion area. The cerebral blood flow measurement indicates that the administration of Xe-NBs can improve microcirculatory restoration, resulting in reduced acute microvascular injury in the lesion area. Furthermore, local delivery of therapeutic Xe can significantly reduce the volume of cerebral infarction and restore the neurological function with reduced neuron injury against apoptosis. Therefore, Xe-NBs provide a novel nanosystem for the safe and rapid theranostics of acute ischemic stroke, which is promising to translate into the clinical management of stroke.