Li Xingyu, Tang Zhaoxia, Kuang Liangjian, Wu Yongjian, Huang Xi
Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, Guangdong, China.
Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China.
J Transl Med. 2025 Jul 25;23(1):841. doi: 10.1186/s12967-025-06649-2.
Platelets play a critical role in the pathophysiology of acute lung injury (ALI) by activating neutrophils and promoting the formation of neutrophil extracellular traps (NETs). Excessive NETs formation exacerbates lung injury by triggering inflammation, impairing essential alveolar macrophage functions and activating the coagulation cascade. Consequently, inhibiting NETs formation represents a promising strategy for treating ALI.
In this study, we developed platelet membrane-coated nanoparticles (PNPs) by encapsulating poly(lactic-co-glycolic acid, PLGA) nanoparticles within platelet membranes, and we characterized their physicochemical and functional properties. We investigated the effects of PNPs on platelet activation, NETs formation, mitochondrial ROS (mtROS) production and Syk phosphorylation in vitro. Furthermore, we evaluated the therapeutic effects of PNPs on acute lung inflammatory responses in a murine model.
Compared with red blood cell membrane-coated nanoparticles (RBC-NPs), PNPs significantly inhibited both platelet activation and NETs formation. Mechanistic studies demonstrated that NETs generation was markedly attenuated via CD62P signaling inhibition in platelets and mitochondrial ROS scavenging in neutrophils (using mito-TEMPO), and these treatments exhibited a suppression efficiency that was comparable to that of PNPs treatment. In vivo experiments revealed that PNPs preferentially accumulated in the lungs of mice with ALI, reducing neutrophil infiltration and NETs formation. Furthermore, PNP treatment attenuated lung injury, as evidenced by reduced collagen deposition, decreased total protein levels and cell numbers in BALF, and decreased levels of proinflammatory cytokines in the lungs.
Our findings demonstrate that PNPs have potential for use in treating ALI by simultaneously attenuating platelet activation and NETs formation.
血小板通过激活中性粒细胞和促进中性粒细胞胞外诱捕网（NETs）的形成，在急性肺损伤（ALI）的病理生理学中发挥关键作用。过量的NETs形成通过引发炎症、损害重要的肺泡巨噬细胞功能和激活凝血级联反应，加剧肺损伤。因此，抑制NETs形成是治疗ALI的一种有前景的策略。
在本研究中，我们通过将聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒包裹在血小板膜内，制备了血小板膜包被纳米颗粒（PNPs），并对其理化和功能特性进行了表征。我们在体外研究了PNPs对血小板激活、NETs形成、线粒体活性氧（mtROS）产生和脾酪氨酸激酶（Syk）磷酸化的影响。此外，我们在小鼠模型中评估了PNPs对急性肺部炎症反应的治疗效果。
与红细胞膜包被纳米颗粒（RBC-NPs）相比，PNPs显著抑制了血小板激活和NETs形成。机制研究表明，通过抑制血小板中的CD62P信号传导和清除中性粒细胞中的线粒体ROS（使用线粒体靶向抗氧化剂mito-TEMPO），NETs的生成明显减弱，这些处理表现出与PNPs处理相当的抑制效率。体内实验表明，PNPs优先在ALI小鼠的肺中积聚，减少中性粒细胞浸润和NETs形成。此外，PNPs治疗减轻了肺损伤，表现为胶原沉积减少、支气管肺泡灌洗液（BALF）中总蛋白水平和细胞数量降低以及肺中促炎细胞因子水平降低。
我们的研究结果表明，PNPs通过同时减弱血小板激活和NETs形成，具有治疗ALI的潜力。
