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Nat Nanotechnol. 2017 Jul;12(7):701-710. doi: 10.1038/nnano.2017.56. Epub 2017 Apr 24.

Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices.

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Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain.
Institute of Biomaterials and Biomedical Engineering, Departments of Chemistry, Chemical Engineering, and Materials Sciences and Engineering, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
Department of Physiology, McGill University, McIntyre Medical Building, Montreal, Quebec H3G 1Y6, Canada.
Departments of Cell Biology and Anatomy, and Pathology &Laboratory Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Environmental &Molecular Toxicology Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvalis, Oregon 97333, USA.
Center for Modeling Human Disease, Toronto Centre for Phenogenomics, Lunenfeld Research Institute, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada.


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.

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