A Thrombin-Activated Peptide-Templated Nanozyme for Remedying Ischemic Stroke via Thrombolytic and Neuroprotective Actions.

Abstract

Ischemic stroke (IS) is one of the most common causes of disability and death. Thrombolysis and neuroprotection are two current major therapeutic strategies to overcome ischemic and reperfusion damage. In this work, a novel peptide-templated manganese dioxide nanozyme (PNzyme/MnO2 ) is designed that integrates the thrombolytic activity of functional peptides with the reactive oxygen species scavenging ability of nanozymes. Through self-assembled polypeptides that contain multiple functional motifs, the novel peptide-templated nanozyme is able to bind fibrin in the thrombus, cross the blood-brain barrier, and finally accumulate in the ischemic neuronal tissues, where the thrombolytic motif is "switched-on" by the action of thrombin. In mice and rat IS models, the PNzyme/MnO2 prolongs the blood-circulation time and exhibits strong thrombolytic action, and reduces the ischemic damages in brain tissues. Moreover, this peptide-templated nanozyme also effectively inhibits the activation of astrocytes and the secretion of proinflammatory cytokines. These data indicate that the rationally designed PNzyme/MnO2 nanozyme exerts both thrombolytic and neuroprotective actions. Giving its long half-life in the blood and ability to target brain thrombi, the biocompatible nanozyme may serve as a novel therapeutic agent to improve the efficacy and prevent secondary thrombosis during the treatment of IS.