Endoplasmic Reticulum Stress-Triggered Autophagy and Lysosomal Dysfunction Contribute to the Cytotoxicity of Amine-Modified Silver Nanoparticles in NIH 3T3 Cells

The mechanisms underlying nanoparticle-induced toxicity have become one of the most studied topics in toxicology during the last few years. Because of their excellent antimicrobial activity, silver nanoparticles (AgNPs) are recognized as promising nanomaterials with broad applicability. However, knowledge of the impact of AgNPs on biological systems, particularly regarding their possible effects and fate in living cells remains limited. Amines are among most popular AgNPs modifying agents. In this study, we found that amine-modified AgNPs could be taken up by cells through endocytosis. The internalized AgNPs eventually accumulated in lysosomes or autophagosomes. Smaller AgNPs (SAS, similar to 20 nm) were more toxic than larger AgNPs (LAS, similar to 80 nm). Our results suggest that SAS caused more lysosomal swelling, arrested autophagy and cell death. The mechanisms underlying the AgNP-induced autophagy in NIH 3T3 cells could be mediated by the activation of oxidative stress and endoplasmic reticulum (ER) stress signaling pathways. AgNPs treatment could trigger the expression of ER stress and autophagy markers (IRE1 and LC3-II). However, the autophagy substrate, p62, was accumulated in AgNP-treated cells, indicating that the autophagy process was inhibited. Our results clarify the mechanism by which AgNPs induce autophagosome accumulation and reveal the effects of AgNPs on lysosomes. This study illustrates the influence of AgNPs on biological systems and may provide insights to guide the development of protective measures for biomedical applications of AgNPs.