A Novel Metal‐Phenolic‐Protein Hybrid Nanoparticles With Precise Delivery and Enhanced Penetration Effect for tPA Targeted Thrombolysis and Reduced Hemorrhagic Risk

ABSTRACT Ischemic stroke (IS) is a leading cause of mortality and disability worldwide, posing a critical public health challenge. Currently, clinical use of tissue plasminogen activator (tPA) for IS thrombolytic treatment remains many problems in outcomes and safety, particularly the high risk of hemorrhagic transformation. Here, a metal‐phenolic network (MPN)‐based nanoparticle hybrid tPA and targeting ligand (MPN@tPA@GP) is developed for tPA targeting delivery to local thrombus interior, achieving efficient pH‐sensitive tPA release and reduced hemorrhage risk for IS therapy. The binding and penetrating thrombi efficiency of 8 fibrin‐targeting peptides is screened in different types of thrombi made from human blood in vitro. The construction of a hybrid nanoparticle with tPA and GP targeting peptide (MPN@tPA@GP) can be achieved through a simple self‐assembly process and confirmed by FTIR, EDS, SDS‐PAGE, and disrupting agents, while Mg 2 ⁺ coordination is believed as the critical force in nanoparticle formation. This nanoparticle exhibited good fibrinolytic activity and pH‐responsive tPA release in vitro. In vivo targeting studies revealed excellent thrombus binding and penetrating capability in two animal models. Furthermore, MPN@tPA@GP displayed superior therapeutic efficacy with a reduced tPA‐induced hemorrhage risk, resulting from excellent thrombus targeting, pH‐responsive release, and Magnesium homeostasis maintenance. Thus, this nanoparticle offers a promising strategy to improve the efficacy and reduce the hemorrhage risk of thrombolytic therapy for IS.