Nanodiamonds Interact with Primary Human Macrophages and Dendritic Cells Evoking a Vigorous Interferon Response

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.