Molecular mechanisms of silver nanoparticle-induced neurotoxic injury and new perspectives for its neurotoxicity studies: A critical review

Silver nanoparticles (AgNPs) garnered significant attention and applications in the field of nanotechnology due to their unique physicochemical properties. However, with the increasing exposure of AgNPs in the environment and biological systems, concerns about their potential neurotoxicity have also risen. Recent studies on the neurotoxic effects and mechanisms of AgNPs have often relied on traditional toxicological research methods and perspectives. This reliance has limited the extrapolation of these findings to the human brain environment and hindered a deep understanding of the neurotoxicity of AgNPs. This review first outlines the molecular mechanisms of AgNPs-induced neurotoxic injury from a traditional research perspective, identifying oxidative stress, inflammatory responses, and autophagy disorders as key areas of current research. Related molecular signaling pathways, including the nuclear transcription factor-κB (NF-κB) signaling pathway, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the calcium signaling pathway, have been implicated in the neurotoxic injury process induced by AgNPs. Subsequently, we elucidated the unique advantages of the 3D brain organoids applied to the neurotoxicity study of AgNPs by drawing on relevant studies in the same field. We also emphasize that establishing a standardized 3D brain organoids construction platform is a crucial prerequisite for its widespread application. Furthermore, we suggest that future studies should explore the neurotoxicity mechanisms of AgNPs through the lenses of “adaptive homeostasis” and “structure-activity relationship analysis”. In conclusion, the neurotoxicity of AgNPs should be comprehensively evaluated by integrating new research techniques and perspectives, ultimately allowing these nanoparticles to better serve human society.