Extracellular Vesicle Properties and Functions Are Defined by the Originating Cell's Fitness Status

Recent studies have focused on the role of dying cells in modulating immune function and shaping the local microenvironment. Apoptotic cells release various extracellular vesicles (EVs), such as exosomes and microvesicles, and form apoptotic bodies through membrane blebbing. Despite growing interest in EVs, the effects of EVs derived from apoptotic cells versus those from live cell remain poorly understood. Here, via transmission electron microscopy, nanoparticle tracking analysis, proteomics, and flow cytometry, we characterise the distinct features of EVs from live versus apoptotic cells. Using a model of <i>Schistosoma mansoni</i> infection, characterised by the presence of dying cells due to parasite egg accumulation, we demonstrate that the injection of apoptotic T cell-derived EVs attenuates hepatocyte damage, in contrast to EVs from live T cells. Analysis of the transcriptomic profile of target macrophages and functional assays revealed that apoptotic cell-derived EVs activate nitric oxide-related pathways, which modulate macrophage function. Furthermore, these EVs specifically promoted fibroblast-mediated wound healing in vitro. Collectively, our findings highlight that cell fitness influences EV properties and their immune regulatory function. Investigating the differences between EVs from living and apoptotic cells is essential for advancing our understanding of immune regulation and optimising the development of EV-based therapeutic strategies.