tPLGA nanoparticles combined with CCL2/CCR2 inhibitor mitigate post-thrombolytic hemorrhagic transformation

Abstract

Ischemic stroke continues to be a leading cause of death and long-term disability worldwide. However, the clinical use of intravenous tissue plasminogen activator (tPA) is constrained by its rapid systemic clearance and the risk of hemorrhagic transformation (HT). In this study, we present an MMP-9-responsive PLGA-based nanocarrier (tPLGA) that enables thrombus-microenvironment triggered release of tPA. When combined with Bindarit, an inhibitor of the CCL2/CCR2 pathway, this strategy achieves both targeted thrombolysis and effective suppression of HT. In mouse thrombosis models, tPLGA mediated precise spatiotemporal tPA delivery, enhancing clot dissolution. Concurrent CCL2/CCR2 blockade reduced neutrophil infiltration, preserved blood–brain barrier (BBB) integrity, and prevented HT. Behavioral, histological, and biosafety assessments confirmed improved neurological recovery and translational potential. This work establishes a therapeutic platform integrating precision thrombolysis with immune modulation for a safer and more effective treatment of ischemic stroke.