Hemocompatible Glycogen‐Tissue Plasminogen Activator Complexes for Enhanced Blood Clot Dissolution

Thrombosis and embolism remain leading causes of death worldwide, driven by blood clots that obstruct vascular flow. Current treatments rely on intravenous injections of tissue plasminogen activator (tPA) to dissolve clots, however, free tPA has severe limitations, including poor targeting, and risks of bleeding and hemorrhage. In this work, we look to overcome these limitations with targeted, biodegradable, and hemocompatible glycogen nanoparticles. We develop glycogen–heparin hybrids for complexation with tPA, along with peptide‐based targeting towards activated platelets. Our strategy involves leveraging the inherent hemocompatibility of glycogen, with minimal synthetic modifications for targeted delivery of tPA to blood clots. In human blood, the glycogen hybrids have minimal interaction with immune cells, and did not trigger inflammatory or coagulation responses at therapeutic concentrations. Furthermore, they remain biodegradable towards glucosidases inherently in the human body. This design enables thrombus targeting and localized tPA delivery, thereby improving fibrinolytic efficiency relative to free tPA, with steady breakdown kinetics. This was also observed for blood clots subjected to thrombolysis under vascular flow‐like conditions. Overall, our approach offers a promising treatment strategy for thrombosis, which improves the therapeutic efficacy of tPA, whilst maintaining excellent hemocomptability.