Gold Nanorods Induce Endoplasmic Reticulum Stress and Autocrine Inflammatory Activation in Human Neutrophils

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 alpha (IRE alpha) 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.

Automated summary

This study investigates the uptake, intracellular processing, and cell biological response induced by AuNRs in PMNs, demonstrating that AuNRs mainly enter cells through phagocytosis and macropinocytosis, leading to protein stress and pro-inflammatory response.