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Extracellular vesicles large-scale production is a crucial point for the translation of EVs from discovery to application of EV-based products. In October 2021, the International Society for Extracellular Vesicles (ISEV), along with support by the FET-OPEN projects, evFOUNDRY and VES4US, organized a workshop entitled "massivEVs" to discuss the potential challenges for translation of EV-based products. This report gives an overview of the topics discussed during "massivEVs", the most important points raised, and the points of consensus reached after active discussion among academia and industry representatives. Overall, the review of the existing EV manufacturing and upscaling challenges and the directions for their resolution highlighted in the workshop was constructive and painted an optimistic future for the dynamically expanding EV field.

Previous studies have demonstrated that transient myocardial ischemia leads to release of cellular nucleic acids such as RNA. Extracellular RNA reportedly plays a pivotal role in myocardial inflammation and ischemic injury in animals. RNA profiling has identified that numerous microRNA (miRNAs), such as ss-miR-146a-5p, are upregulated in plasma following myocardial ischemia, and certain uridine-rich miRNAs exhibit strong proinflammatory effects in immune cells via ssRNA-sensing mechanism. However, the effect of extracellular miRNAs on myocardial inflammation and cardiac cell function remains unknown. In this study, we treated adult mouse cardiomyocytes with miR-146a-5p loaded in extracellular vesicles and observed a dose-and TLR7-dependent production of CXCL-2, IL-6, and TNF-a. In vivo, a single dose of myocardial injection of miR-146a-5p induced both cytokine expression (CXCL2, IL-6, and TNF-a) and innate immune cell activation (CD45 + leukocytes, Ly6C mid+ monocytes, Ly6G + neutrophils), which was significantly attenuated in the hearts of TLR7 KO mice. We discovered that conditioned media from miR-146a-treated macrophages stimulated proinflammatory cytokine production in adult cardiomyocytes and significantly inhibited their sarcomere shortening. Finally, using an electric cell impedance-sensing assay, we found that the conditioned media from miR-146a-treated cardiac fibroblasts or cardiomyocytes impaired the barrier function of coronary artery endothelial cells. Taken together, these data demonstrate that extracellular miR-146a-5p activates multiple cardiac cells and induces myocardial inflammation and cardiomyocyte dysfunction via intercellular interaction and innate immune TLR7 nucleic acid sensing. ImmunoHorizons, 2020, 4: 561-572.

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