Chen Sa, Wu Aijia, Shen Xinran, Kong Jinxia, Huang Yuan
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China..
J Control Release. 2025 Mar 10;379:814-831. doi: 10.1016/j.jconrel.2025.01.053. Epub 2025 Jan 28.
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.
脓毒症是一种危及生命的疾病，其特征为全身性炎症反应过度和凝血病。血小板和中性粒细胞通过相互作用形成“危险联盟”，在脓毒症期间促进炎症细胞因子风暴和凝血紊乱。血小板 - 中性粒细胞相互作用导致血小板 - 中性粒细胞复合物（PNC）的形成，而这些复合物是这个“危险联盟”的核心“主角”。这些PNC进一步增强血小板与中性粒细胞之间的相互作用，通过正反馈回路放大免疫和凝血反应。尽管最近报道了一些靶向治疗方法，但它们主要集中在诱导中性粒细胞凋亡或降解现有的中性粒细胞胞外陷阱（NETs）。针对血小板并抑制脓毒症相关PNC的策略有限。在此，我们提出一种双管齐下的方法，通过将药物同时靶向“危险联盟”中的血小板和中性粒细胞来阻断血小板 - 中性粒细胞相互作用。该策略不仅有效减轻了血小板 - 中性粒细胞相互作用诱导的炎症，还减少了PNC的形成，从而拆除了微血栓的结构支架。在脓毒症小鼠模型中，这种方法显著降低了血小板 - 中性粒细胞相互作用的标志物，减少了细胞因子风暴，并降低了血栓形成的风险。此外，它减轻了PNC浸润引起的器官损伤，并延长了脓毒症小鼠的生存期。总体而言，这项工作结合了抗炎和抗凝疗法，有效地破坏了血小板与中性粒细胞之间的“危险联盟”，为治疗脓毒症提供了一种有前景的策略。
