Adverse Outcome Pathway-Based Strategies to Mitigate Ag2Se Quantum Dot-Induced Neurotoxicity

Silver selenide quantum dots (Ag₂Se QDs) show great advantages in tumor imaging due to their excellent optical performance and good biocompatibility. However, the ultrasmall particle size of Ag₂Se QDs allows them to cross the blood–brain barrier, thus potentially affecting the central nervous system. Therefore, risk assessment and response strategies for Ag₂Se QDs are important. The adverse outcome pathway (AOP) framework makes it possible to develop risk management strategies based on toxicity mechanisms. In this study, using the AOP framework, we constructed causal mechanism relationship diagrams at different biological levels of Ag₂Se QD neurotoxicity. In this framework, excess mitochondrial reactive oxygen species (mtROS) triggered Nod-like receptor protein 3 (NLRP3) inflammasome activation in microglia was molecular initiation event (MIE). Proinflammatory mediator secretion and microglia activation were key events (KEs) at the cellular level. Neuroinflammation and neuronal damage were KEs at the organ/tissue level. Altered hippocampal physiology was the adverse outcome (AO) at the individual level. Based on the established AOP framework, further studies confirmed that mtROS-activated nuclear-factor-E2-related factor 2 (Nrf2)/PTEN-induced kinase 1 (PINK1)- mitophagy contributed to weaken the MIE. Molecular docking-assisted molecular biology experiments demonstrated that quercetin (Qu) enhanced this process. This article emphasizes the importance of the AOP in the risk management of nanomaterials. Furthermore, this paper guides the use of natural small-molecule drugs as a strategy to mitigate nanomaterial-induced neurotoxicity.