Clickable liposomes for on-demand reversal of antiplatelet drugs: Towards a safe management of bleeding risks associated with antithrombotic therapy

Antithrombotic drugs are widely used to prevent thrombotic events in patients with cardiovascular diseases. However, they all carry varying degrees of bleeding risk. Currently, there are no approved reversal agents for antiplatelet medications, which limits their further clinical application and poses challenges in managing bleeding complications. In this proof-of-concept study, we explore the feasibility of a reversal agent system using ticagrelor and a corresponding liposome-based antidote. Specifically, we developed an azide-functionalized ticagrelor derivative (TicN₃) and a clickable DBCO-modified liposome (Lipo-DBCO) to enable controlled reversal of antiplatelet activity. Our findings demonstrate that the azide modification does not compromise the antiplatelet efficacy and biocompatibility of ticagrelor. The antiplatelet effects of Tic-N₃ were successfully reversed by Lipo-DBCO, as validated through platelet aggregation assays and in vivo mouse models of tail bleeding and liver injury. Additionally, we investigated the thiol-maleimide pairing as an alternative system, enhancing the versatility of our approach. This strategy reveals the possibility and clinical application prospects of antiplatelet drug reversal agents, offering a promising solution for the safe management of bleeding risks associated with antiplatelet therapy.