Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA–protein nanoparticulates in the pathobiology of autoimmune diseases.

纳米技术能够研究单个生物大分子，但技术挑战限制了在液体活检（例如血浆）中的应用。尽管如此，随着人们越来越认识到纳米尺度蛋白质结构变化的生理重要性，用于表征此类样品中单个分子种类的工具代表了一个重要的未满足需求。甘露糖结合凝集素 (MBL) 是一种寡聚血浆蛋白，通过其激活补体的能力成为先天免疫系统的一部分。MBL 还可以作为细胞碎片，尤其是 DNA 的清除剂。这可能将 MBL 的功能与几种炎症性疾病联系起来，其中无细胞 DNA 现在似乎发挥了作用，但一直缺乏机制洞察力。通过在人体血浆中进行纳米粒子追踪分析，我们现在表明 MBL 的超寡聚结构与 DNA 形成纳米颗粒。这些寡聚体与系统性红斑狼疮患者的疾病活动相关。通过对流体动力学半径的直接量化，遵循血流中泰勒分散原理的计算将这些复合物的大小与内皮炎症联系起来，这是狼疮中最重要的发病率之一。来自狼疮动物模型的机械见解支持 DNA 稳定的超寡聚体刺激生发中心 B 细胞的形成并导致免疫耐受性的丧失。这种形成涉及 MBL 超寡聚体的浓度与双链 DNA 抗体之间的反比关系。