Supramolecular Prodrug Hydrogel for One‐Week Protection Against Thrombosis

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.