"Iron -free" CdSe/ZnS quantum dots disrupt neural differentiation of embryonic stem cells via the induction of ferroptosis.

Exposure to Cadmium-based quantum dots (QDs) is becoming a growing threat to human health, necessitating a deeper understanding of their intracellular behavior and the associated toxic effects. Among the various domains of nanosafety assessment, the impact of these QDs on the nervous system is particularly critical; however, the potential effects on neurodevelopment and the underlying mechanisms remain largely unexplored. The current study explores the neural developmental toxicities associated with exposure to QDs made of cadmium selenide (CdSe) and encapsulated within a zinc sulfide (ZnS) shell using mouse embryonic stem cells (mESCs). Exposure to CdSe/ZnS QDs was found to impair the neural differentiation of mESCs via a novel mechanism of programmed cell death known as ferroptosis. Specifically, the CdSe/ZnS QDs were found to be internalized by cells, with a substantial fraction remaining within the cells even after a 24 h clearance period. Furthermore, nanoparticle internalization induced significant ROS/MDA elevation, mitochondrial depolarization and intracellular iron overload, collectively triggering ferroptosis and consequent tricarboxylic acid (TCA) cycle dysfunction. Importantly, the application of ferroptosis inhibitors was found to alleviate the disruption in the TCA cycle induced by CdSe/ZnS QDs and restore neural differentiation. Additionally, ferroptosis was established as a common form of cell death triggered by nanoparticles. These findings underscore the urgent need for further investigations into the safety profiles of CdSe/ZnS QDs in a neurological context, as an understanding of the underlying mechanisms can facilitate informed risk assessments and guide the development of safer nanomaterials for biomedical applications.