Supramolecular Prodrug Hydrogel for One‐Week Protection Against Thrombosis

Abstract In clinical anticoagulant therapy, the drug Bivalirudin (Biva) presents a lower incidence of adverse events and more predictable pharmacokinetics in comparison to heparin. However, its short half‐life of ≈20 min leads to poor patient compliance and increased medical burden. Here, a long‐acting anticoagulant hydrogel based on Biva for antithrombotic treatment is described. The fusion peptide ( d ‐RADA)8‐B that integrates Biva, a D‐type self‐assembly motif, and an activated factor X (FXa)‐responsive motif exhibits both supramolecular reservoir and prodrug‐like properties. After subcutaneous injection, the anticoagulant peptide forms a semi‐solid depot with protease‐degradation resistance and slowly disassembles to release prodrug ( d ‐RADA)8‐B into the bloodstream. The circulating prodrug acts as an inert sentinel, which can be activated to release Biva to inhibit thrombus formation when exposed to the thrombus‐related protease FXa. One week after the administration of ( d ‐RADA)8‐B, significant embolism suppression is observed in animal models of carotid artery thrombosis and pulmonary embolism without increasing hemorrhagic side effects. This study demonstrates a concise strategy to engineer a supramolecular anticoagulant hydrogel with long‐term, high drug loading, and on‐demand antithrombotic activation.