A Biomimetic Zeolite-based Nanoenzyme Contributes to Neuroprotection in the Neurovascular Unit After Ischaemic Stroke Via Efficient Removal of Zinc and ROS

Zeolite-based nanomaterials have a large number of applications in the field of medicine due to their high porosity, biocompatibility and biological stability. In this study, we designed cerium (Ce)-doped Linde Type A (LTA) zeolite-based nanomaterials (Ce/Zeo-NMs) as a multifunctional mesoporous nanoenzyme to reduce dysfunction of the neurovascular unit (NVU) and attenuate cerebral ischaemia-reperfusion (I/R) injury. Owing to its unique adsorption capacity and mimetic catalytic activities, Ce@Zeo-NMs adsorbed excess zinc ions and exhibited scavenging activity against reactive oxygen species (ROS) induced by acute I/R, thus reshaping the oxidative and zinc microenvironment in the ischaemic brain. In vivo results demonstrated that Ce@Zeo-NMs significantly reduced ischaemic damage to the NVU by decreasing the infarct area, protecting against breakdown of the blood-brain barrier (BBB) via inhibiting the degradation of tight junction proteins (TJPs) and inhibiting activation of microglia and astrocytes in a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R). Taken together, these findings indicated that Ce@Zeo-NMs may serve as a promising dual-targeting therapeutic agent for alleviating cerebral I/R injury. STATEMENT OF SIGNIFICANCE: Cerium (Ce)-doped Linde Type A zeolite-based nanomaterials (Ce/Zeo-NMs) as a multifunctional mesoporous nanoenzyme were designed for inducing neuroprotection after ischaemic stroke by reducing dysfunction of the neurovascular unit (NVU). Ce@Zeo-NMs had the ability to adsorb excessive Zn and showed mimetic enzymatic activities. As a result, Ce@Zeo-NMs protected against cerebral ischaemia and reduced the damage of NVU by improving the integrity of blood brain barrier (BBB) and inhibiting activation of microglia and astrocytes in a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R). These findings indicated that Ce@Zeo-NMs may serve as a therapeutic strategy for neuroprotection and functional recovery upon ischaemic stroke onset.