Anticoagulant therapy without bleeding: A novel molybdenum-based nanodots alleviate lethal coagulation in bacterial sepsis by inhibiting ROS-facilitated caspase-11 activation

Abstract

Sepsis is a leading cause of death worldwide. This syndrome is commonly accompanied by overactivation of coagulation, excessive reactive oxygen species (ROS), and inflammatory cytokine storm. Notably, disseminated intravascular coagulation (DIC) accounts for around 40% of sepsis-associated deaths. However, anticoagulant therapy is still difficult for sepsis treatment because of the lethal bleeding side effects. Although the relationship between ROS and inflammatory cytokine storm has been described clearly, the pathogenic role of ROS in DIC, however, is still unclear, which renders novel therapeutic approaches hard to achieve bedside for inhibiting DIC. Herein, our new finding reveals that ROS greatly facilitates the entry of lipopolysaccharide (LPS) into the macrophage cytoplasm, which subsequently activates the caspase-11/gasdermin D pathway, and finally induces DIC through phosphatidylserine exposure. Based on this finding, novel gallic acid-modified Mo-based polyoxometalate dots (M-dots) with outstanding antioxidant activity are developed to provide ideal and efficient inhibition of DIC. As expected, M-dots are capable of markedly inhibiting sepsis-caused coagulation, organ injury, and death in sepsis. This therapeutic strategy, blocking the upstream pathway of coagulation rather than coagulation itself, can avoid the side effects of extensive bleeding caused by conventional anticoagulation therapy, and will provide a new avenue for the efficient treatment of sepsis.

Keywords

caspase-11 / coagulation / gallic acid-modified Mo-based polyoxometalate dots / lipopolysaccharide internalization / reactive oxygen species scavenger / sepsis

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