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

Abstract

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.

N1 versus N2 and PMN‐MDSC: A critical appraisal of current concepts on tumor‐associated neutrophils and new directions for human oncology

“…For example, the exposure of PMN to gold nanoparticles induces metabolic changes and ER stress, which promotes proinflammatory autocrine loop of IL-8 and LOX-1 expression. 139 Using scRNA-seq analysis in a murine breast cancer model, significant overlap between M-MDSC and PMN-MDSC isolated from the spleens and tumors was shown. Shared genes associated with immunosuppressive features were CD84, Arg1, IL1B, and Wfdc17…”

“…In addition, although LOX‐1 expression is reported on PMN‐MDSC in different cancer types, 91 it is also upregulated on neutrophils in healthy subjects during activation and cellular stress. For example, the exposure of PMN to gold nanoparticles induces metabolic changes and ER stress, which promotes pro‐inflammatory autocrine loop of IL‐8 and LOX‐1 expression 139 …”

Biomaterials for Targeting Endoplasmic Reticulum in Cancer

“…This study provided an understanding of the interaction between AuNR and the immune cells for a potential therapeutic strategy. [77] One of the important applications of AuNPs in biomedicine is their ability to induce photothermal effect under irradiation with laser light of different wavelengths. [78] To explore the photothermal effect, Lancu et al developed albumin coated Au-NPs and treated HepG2 hepatocellular carcinoma cells under 808 nm laser light.…”

Surface Geometry of Cargo-less Gold Nanoparticles Is a Driving Force for Selective Targeting of Activated Neutrophils to Reduce Thrombosis in Antiphospholipid Syndrome

“… 22 − 24 Particle topology can alter the affinity of functionalized surfaces to targeted cells, 25 yet certain shapes can induce detrimental reactive oxygen species (ROS) production. 23 In this study, we optimized the nanoparticle shape and surface chemistry to improve the selectivity for clustered PSGL-1 on neutrophils, and we showed that star-shaped anti-PSGL-1-antibody-coated gold nanoparticles (aPSGL-1-AuNPs) mitigated thrombosis in APS mice through targeting PSGL-1 clusters. Importantly, this thromboprotective effect was not associated with an increase in the bleeding risk.…”

“…While the concept of reducing thrombosis via targeting neutrophil PSGL-1 clusters is achievable, we aim to develop a more sufficient biocompatible nanoparticle to accomplish the goal. Gold nanoparticles (AuNPs) were the first metal-based nanocarriers approved by the FDA and were widely studied in tumor imaging and drug delivery to cancer cells. , The established synthetic approaches allows for modification of particle topology to generate spherical, cubic, rod-like, disc, triangle, and star-like shapes of AuNPs. − Several studies indicated that the shape of nanoparticles has substantial yet not always the same effect on particle uptake and immune response. − Particle topology can alter the affinity of functionalized surfaces to targeted cells, yet certain shapes can induce detrimental reactive oxygen species (ROS) production . In this study, we optimized the nanoparticle shape and surface chemistry to improve the selectivity for clustered PSGL-1 on neutrophils, and we showed that star-shaped anti-PSGL-1-antibody-coated gold nanoparticles (aPSGL-1-AuNPs) mitigated thrombosis in APS mice through targeting PSGL-1 clusters.…”