Disrupting the dangerous alliance: Dual anti-inflammatory and anticoagulant strategy targets platelet-neutrophil crosstalk in sepsis.

Sepsis is a life-threatening disease characterized by excessive systemic inflammation and coagulopathy. Platelets and neutrophils form a "dangerous alliance" through crosstalk, promoting the inflammatory cytokine storm and coagulation disorders during sepsis. Platelet-neutrophil crosstalk leads to the formation of platelet-neutrophil complexes (PNCs), which are the central "protagonists" of this "dangerous alliance." These PNCs further enhance the crosstalk between platelets and neutrophils, amplifying immune and coagulation responses through positive feedback loops. Although some targeted therapies have been reported recently, they primarily focus on inducing neutrophil apoptosis or degrading existing neutrophil extracellular traps (NETs). Limited strategies are available for targeting platelets and suppressing sepsis-associated PNCs. Herein, we propose a two-pronged approach to intercept platelet-neutrophil crosstalk by simultaneously targeting drugs to both platelets and neutrophils of the "dangerous alliance." This strategy not only effectively alleviates inflammation induced by platelet-neutrophil crosstalk but also reduces PNC formation, thereby dismantling the structural scaffold of microthrombi. In a sepsis mouse model, this approach significantly decreased markers of platelet-neutrophil crosstalk, reduced the cytokine storm, and lowered the risk of thrombosis. Moreover, it alleviated organ damage caused by PNC infiltration and prolonged the survival of septic mice. Overall, this work combines anti-inflammatory and anticoagulant therapies to effectively disrupt the "dangerous alliance" between platelets and neutrophils, offering a promising strategy for treating sepsis.