Thrombus-targeted nanoparticles for thrombin-triggered thrombolysis and local inflammatory microenvironment regulation

Abstract

Thrombus related diseases seriously threaten human's health and life. The drawbacks of thrombolytic drugs, such as poor targeting ability and unexpected bleeding complications limit their clinical application. Thus, targeted delivery and controlled release of drugs at local thrombus sites to achieve efficient thrombolysis is an urgent event to be resolved. Herein, we developed an intelligent system MnO2/uPA@pep-Fuco for precise thrombolysis and thrombus inflammatory microenvironment remodeling. MnO2/uPA@pep-Fuco exhibited an excellent thrombus targeting ability via the high affinity of fucoidan (Fuco) for P-selectin overexpressed by activated platelets. And then pep-Fuco modified onto the surface of mesopore could be removed to release urokinase (uPA) locally under the high level of thrombin microenvironment in thrombus site. Meanwhile, due to the catalase-like activity of MnO2 nanoplatform, MnO2/uPA@pep-Fuco could regulate the inflammatory thrombus microenvironment by eliminating hydrogen peroxide (H2O2), so as to achieve a collaborative thrombolysis therapy. In ferric chloride (FeCl3)-induced carotid thrombus models, MnO2/uPA@pep-Fuco specifically targeted to the obstructive artery (3.43 times that of the normal artery) and significantly decreased the percentage of thrombus closure (5.99 ± 5.07%), demonstrating the superior thrombolysis ability. In addition, the significantly reduced tail bleeding time suggested MnO2/uPA@pep-Fuco might possess a low risk of bleeding complications.