Discoidal nanoparticles exploit thrombus-induced shear gradients to enhance site-specific thrombolysis in stroke

Thromboembolic stroke is characterized by cerebral ischemia caused by arterial thrombosis. Although tissue plasminogen activator (tPA) remains the gold standard for thrombolytic therapy, its clinical use is limited by a narrow therapeutic window and the need for continuous infusion. Nanoparticle-based delivery platforms have been explored to enhance the thrombolytic performance of tPA; however, efficient targeting to thrombus sites remains a key challenge. Notably, thrombosis-induced alterations in blood flow shear stress significantly influence the margination behavior of nanoparticles, which is highly dependent on their morphology and directly impacts thrombus accumulation and lytic efficacy. In this study, we fabricated poly (lactic-co-glycolic acid) (PLGA) nanoparticles with spherical, rod-shaped, and discoidal geometries, and conjugated them with tPA. Among these, discoidal nanoparticles (D-tPA) demonstrated enhanced margination and preferential adhesion to thrombi under high shear conditions, leading to improved thrombolysis and restoration of cerebral perfusion. These findings highlight the critical role of particle shape in vascular drug delivery and position discoidal PLGA nanoparticles as a promising strategy for targeted thrombolytic therapy in ischemic stroke. STATEMENT OF SIGNIFICANCE: This study presents the application of discoidal poly (lactic-co-glycolic acid) (PLGA) nanoparticles for the treatment of thromboembolic stroke, offering an innovative approach to improving drug delivery and thrombolytic efficiency. Compared to spherical or rod-shaped nanoparticles, discoidal nanoparticles exhibit significant margination and thrombus adhesion under high shear stress conditions, thereby enhancing thrombolysis and promoting blood flow restoration. This work opens new avenues for nanomedicine in stroke therapy and holds potential clinical significance for more effective and targeted treatments in vascular diseases.