Hydrogen peroxide-responsive platelet membrane-coated nanoparticles for thrombus therapy

Abstract

Occlusion of blood vessels caused by thrombi is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombi can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (H₂O₂)-scavenging ability. Inspired by the abundance of H₂O₂ and the active thrombus-targeting property of platelets, a H₂O₂-responsive platelet membrane-cloaked argatroban-loaded polymeric nanoparticle (PNP_Arg) was developed for thrombus therapy. Poly(vanillyl alcohol-co-oxalate) (PVAX), a H₂O₂-degradable polymer, was synthesized to form an argatroban-loaded nanocore, which was further coated with platelet membrane. The PNP_Arg can effectively target the blood clots due to the thrombus-homing property of the cloaked platelet membrane, and subsequently exert combined H₂O₂-scavenging effect via the H₂O₂-degradable nanocarrier polymer and antithrombotic effect via argatroban, the released payload. The PNP_Arg effectively scavenged H₂O₂ and protected cells from H₂O₂-induced cellular injury in RAW 264.7 cells and HUVECs. The PNP_Arg rapidly targeted the thrombosed vessels and remarkably suppressed thrombus formation, and the levels of H₂O₂ and inflammatory cytokines in the ferric chloride-induced carotid arterial thrombosis mouse model. Safety assessment indicated good biocompatibility of the PNP_Arg. Taken together, the biomimetic PNP_Arg offers multiple functionalities including thrombus-targeting, antioxidation, and H₂O₂-stimulated antithrombotic action, thereby making it a promising therapeutic nanomedicine for thrombosis diseases.