Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
Department of Pharmacy, University of Chieti - Pescara "G. d'Annunzio", Via dei Vestini 31, I-66100 Chieti, Italy.
Nano Lett. 2020 Jun 10;20(6):4312-4321. doi: 10.1021/acs.nanolett.0c01011. Epub 2020 May 27.
Many PEGylated nanoparticles activate the complement system, which is an integral component of innate immunity. This is of concern as uncontrolled complement activation is potentially detrimental and contributes to disease pathogenesis. Here, it is demonstrated that, in contrast to carboxyPEG-stabilized poly(lactic--glycolic acid) nanoparticles, surface camouflaging with appropriate combinations and proportions of carboxyPEG and methoxyPEG can largely suppress nanoparticle-mediated complement activation through the lectin pathway. This is attributed to the ability of the short, rigid methoxyPEG chains to laterally compress carboxyPEG molecules to become more stretched and assume an extended, random coil configuration. As supported by coarse-grained molecular dynamics simulations, these conformational attributes minimize statistical protein binding/intercalation, thereby affecting sequential dynamic processes in complement convertase assembly. Furthermore, PEG pairing has no additional effect on nanoparticle longevity in the blood and macrophage uptake. PEG pairing significantly overcomes nanoparticle-mediated complement activation without the need for surface functionalization with complement inhibitors.
许多聚乙二醇化纳米颗粒会激活补体系统，补体系统是先天免疫系统的一个组成部分。这令人担忧，因为不受控制的补体激活可能是有害的，并导致疾病发病机制。在这里，与羧基聚乙二醇稳定的聚（乳酸-乙醇酸）纳米颗粒相反，通过适当组合和比例的羧基聚乙二醇和甲氧基聚乙二醇进行表面伪装，可以通过凝集素途径在很大程度上抑制纳米颗粒介导的补体激活。这归因于短而刚性的甲氧基聚乙二醇链能够横向压缩羧基聚乙二醇分子，使其变得更加伸展，并呈现出伸展的随机卷曲构象。粗粒度分子动力学模拟支持了这一观点，这些构象特征最大限度地减少了蛋白质的统计结合/插入，从而影响补体转化酶组装的顺序动态过程。此外，PEG 配对对纳米颗粒在血液中的寿命和巨噬细胞摄取没有额外的影响。PEG 配对显著克服了纳米颗粒介导的补体激活，而不需要用补体抑制剂对表面进行功能化。
