Micrometer-scale tPA beads amplify plasmin generation for enhanced thrombolytic therapy

Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current thrombolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we demonstrate that a remarkably simple adjustment-using micrometer-scale rather than sub-micrometer particles to immobilize tPA-fundamentally improves thrombolysis. By merely increasing the particle diameter from 0.1 to 1.0 μm, we achieve a dramatic shift in lysis dynamics: 1.0 μm tPA-beads generate higher plasmin flux, readily overcome antiplasmin inhibition, and trigger a self-propagating cascade of fibrinolysis. This leads to near-complete clot dissolution at tPA doses nearly 100-fold lower than standard free tPA, both in vitro and in a murine model of acute ischemic stroke. Within minutes, low-dose 1.0 μm tPA beads fully restore blood flow, outperforming conventional therapies. Our results show that simply scaling up particle size can resolve kinetic and transport barriers in thrombolysis, offering a promising advancement in stroke treatment with potential applications in other thrombotic disorders.