Two‐Nanosensor Electrochemical Profiling of Catecholamine Vesicle Interactions With Acute and Chronic Stress Granules in Living Cells

Stress granules (SGs) are dynamic, membrane-less condensates that assemble in response to stress and have been increasingly linked to neurodegenerative disease (NDD) pathology. However, the molecular and functional mechanisms by which stress granules interact with other cellular organelles remain poorly understood. Here, we present a two-nanosensor electrochemical strategy that enables quantitative discrimination of reactive oxygen species (ROS) in SGs and catecholamines in vesicles at single-cell resolution. Using this approach, we distinguished the intracellular effects of acute and chronic SGs in catecholaminergic cells. Chronic SGs induced by prolonged cisplatin stress, contained elevated ROS levels and markedly increased catecholamine storage per vesicle, likely through ROS-mediated homotypic vesicle fusion. In contrast, acute SGs induced by arsenite exhibited negligible effects. We further demonstrate that chronic SGs exhibit features of aged SGs, such as slow ROS release and enhanced redox activity. These results uncover a redox-coupled SG-vesicle interplay modulated by SG aging and identify chronic SGs as endogenous redox-active condensates that may contribute to neurotransmitter dysregulation and neurodegeneration.