We have shown that nanoparticles (NPs) can be used as ligand-multimerization platforms to activate specific cellular receptors in vivo. Nanoparticles coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHC) blunted autoimmune responses by triggering the differentiation and expansion of antigen-specific regulatory T cells in vivo. Here, we define the engineering principles impacting biological activity, detail a synthesis process yielding safe and stable compounds, and visualize how these nanomedicines interact with cognate T cells. We find that the triggering properties of pMHC–NPs are a function of pMHC intermolecular distance and involve the sustained assembly of large antigen receptor microclusters on murine and human cognate T cells. These compounds show no off-target toxicity in zebrafish embryos, do not cause haematological, biochemical or histological abnormalities, and are rapidly captured by phagocytes or processed by the hepatobiliary system. This work lays the groundwork for the design of ligand-based NP formulations to re-program in vivo cellular responses using nanotechnology.

中文翻译：

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基于肽-MHC的自身免疫纳米药物可作为T细胞受体微簇装置

我们已经表明，纳米粒子（NPs）可以用作配体多聚平台，以在体内激活特定的细胞受体。自身免疫疾病相关肽-主要组织相容性复合物（pMHC）包覆的纳米粒子通过触发体内抗原特异性调节性T细胞的分化和扩增而减弱了自身免疫反应。。在这里，我们定义了影响生物活性的工程原理，详述了产生安全，稳定化合物的合成过程，并可视化了这些纳米药物如何与同源T细胞相互作用。我们发现pMHC-NPs的触发特性是pMHC分子间距离的函数，并且涉及鼠和人类同源T细胞上大抗原受体微簇的持续装配。这些化合物在斑马鱼胚胎中没有显示出脱靶毒性，不会引起血液学，生化或组织学异常，并被吞噬细胞迅速捕获或被肝胆系统处理。这项工作为基于配体的NP制剂的设计奠定了基础，以使用纳米技术重新编程体内细胞反应。