Nanodiamonds (NDs) display several attractive features rendering them useful for medical applications such as drug delivery. However, the interactions between NDs and the immune system remain poorly understood. Here, we investigated amino-, carboxyl-, and poly(ethylene glycol) (PEG)-terminated NDs with respect to primary human immune cells. We applied cytometry by time-of-flight (CyToF) to assess the impact on peripheral blood mononuclear cells at the single-cell level, and observed an expansion of plasmacytoid dendritic cells (pDCs) which are critically involved in antiviral responses. Subsequent experiments demonstrated that the NDs were actively internalized, leading to a vigorous type I interferon response involving endosomal Toll-like receptors. ND-NH2 and ND-COOH were more potent than ND-PEG, as evidenced by using TLR reporter cell lines. Computational studies demonstrated that NDs interacted with the ligand-binding domains of TLR7 and TLR9 with high affinity though this was less pronounced for ND-PEG. NDs with varying surface functionalities were also readily taken up by macrophages. To gain further insight, we performed RNA sequencing of a monocyte-like cell line exposed to NDs, and found that the phagosome maturation pathway was significantly affected. Indeed, evidence for lysosomal hyperacidification was obtained in dendritic cells and macrophages exposed to NDs. Moreover, using a reporter cell line, NDs were found to impinge on autophagic flux. However, NDs did not affect viability of any of the cell types studied. This study has shown that NDs subvert dendritic cells leading to an antiviral-like immune response. This has implications not only for drug delivery but also for anticancer vaccines using NDs.

Department of Applied Physics KTH Royal Institute of Technology 106 91 Stockholm Sweden

Department of Biological Sciences Khalifa University of Science and Technology P O Box 127788 Abu Dhabi United Arab Emirates

Department of Biomedical Sciences University of Padua Padua 351 29 Italy

Department of Biosciences and Nutrition Karolinska Institutet 148 13 Huddinge Sweden

Department of Laboratory Medicine Karolinska Institutet 141 52 Huddinge Sweden

Immunology Center of Georgia Augusta University Augusta Georgia 30912 United States

Institute of Environmental Medicine Division of Molecular Toxicology Karolinska Institutet 171 77 Stockholm Sweden

La Jolla Institute for Immunology San Diego California 92037 United States

Nanotechnology Centre Centre for Energy and Environmental Technologies VSB Technical University of Ostrava 708 00 Ostrava Poruba Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University 772 00 Olomouc Czech Republic

Stem Cells and Metabolism Research Program University of Helsinki 00290 Helsinki Finland

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