Gold nanorods (AuNRs)
are promising agents for diverse biomedical
applications such as drug and gene delivery, bioimaging, and cancer
treatment. Upon in vivo application, AuNRs quickly interact with cells
of the immune system. On the basis of their strong intrinsic phagocytic
activity, polymorphonuclear neutrophils (PMNs) are specifically equipped
for the uptake of particulate materials such as AuNRs. Therefore,
understanding the interaction of AuNRs with PMNs is key for the development
of safe and efficient therapeutic applications. In this study, we
investigated the uptake, intracellular processing, and cell biological
response induced by AuNRs in PMNs. We show that uptake of AuNRs mainly
occurs via phagocytosis and macropinocytosis with rapid deposition
of AuNRs in endosomes within 5 min. Within 60 min, AuNR uptake induced
an unfolded protein response (UPR) along with induction of inositol-requiring
enzyme 1 α (IREα) and features of endoplasmic reticulum
(ER) stress. This early response was followed by a pro-inflammatory
autocrine activation loop that involves LOX1 upregulation on the cell
surface and increased secretion of IL8 and MMP9. Our study provides
comprehensive mechanistic insight into the interaction of AuNRs with
immune cells and suggests potential targets to limit the unwanted
immunopathological activation of PMNs during application of AuNRs.
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