A targeted ferritin-microplasmin based thrombolytic nanocage selectively dissolves blood clots

Abstract

The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (mu Pn); CLT recognizes fibrin-fibronectin complexes in clots, mu Pn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-mu Pn) into nanocage structure protects the activated-mu Pn from its circulating inhibitors. Importantly, activated CLT-sFt-mu Pn thrombolytic nanocage showed a prolonged circulatory life over activated-mu Pn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-mu Pn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies. (c) 2018 Elsevier Inc. All rights reserved.