Multifunctional miRNA delivery systems provide synergistic neuroprotection against cerebral ischemia reperfusion injury.

Effectively alleviating cerebral ischemia-reperfusion (I/R) injury is challenging despite the medical advances. Prompt restoration of blood flow after ischemic stroke causes secondary damage to the brain tissues, triggers neuroinflammation and overproduces reactive oxygen species (ROS). MiRNA regulates the genes involved in neuron apoptosis and neuroinflammation, thus exhibiting potential in ameliorating cerebral I/R injury. However, as miRNA is vulnerable to degradation, its effective delivery faces obstacles in clinical applications. Inspired by the therapeutic potential of miR-210 inhibitors in ischemic stroke-induced neuroinflammation, we constructed a multifunctional nanosystem composed of ceria nanozymes and zeolitic imidazolate framework-90 (ZIF-90) nanoparticles to deliver miR-210 inhibitors to treat cerebral I/R injury. Attributed to the proton sponge effect of ZIF-90, this nanosystem allows for the lysosome escape of miR-210 inhibitors to protect their intracellular bioactivity, while the integration of ZIF-90 and ceria nanozymes utilizes multi-enzyme cascade activities to constrain lipid peroxidation and reduce oxidative damage in brain tissues of mice with middle cerebral artery occlusion (MCAO). After crossing the blood-brain barrier, miR-210 inhibitors target TET2 to suppress pro-inflammatory cytokines, finally inhibiting neuroinflammation. More than the uncertain stability and efficacy of direct TET2 protein administration, the delivery of miR-210 inhibitors by multifunctional nanosystems engendered neuroprotection, indicating their potential for protein replacement therapy against cerebral I/R injury.