Mesoporous Silica Nanotraps for Mitigating Bleeding Risk From ‘Irreversible’ Antiplatelet Drugs

Abstract

The severe bleeding complications of long-term antiplatelet therapy limit its broader application in the treatment or prevention of thrombosis-associated diseases. This risk is particularly serious when facing emergency surgeries where rapid restoration of normal platelet function is required. Timely reversal of the effects of antiplatelet agents becomes crucial in such scenarios. Despite the widespread use of clopidogrel and prasugrel for their potent antiplatelet activity, the absence of specific and effective reversal agents remains a notable challenge. The pharmacological activity of clopidogrel and prasugrel is mediated by sulfhydryl-containing active metabolites, which form disulfide bonds with P2Y₁₂ receptors on the surface of platelets to inhibit their aggregation. Taking advantage of this action mechanism of these “irreversible” antiplatelet drugs, click chemistry-functionalized mesoporous silica (SiO₂-Mal) nanotraps are fabricated to capture the antiplatelet drugs' active metabolites and restore hemostasis. Subsequently, a comprehensive assessment of the effectiveness and safety of the SiO₂-Mal nanotraps is conducted using mouse, rabbit, and pig animal models, highlighting their potential application as a functional reversal agent for clinically relevant thienopyridine antiplatelet drugs, believed until now to be irreversible in their inhibition of platelet activity.