SPLEVs, a new therapeutic modality for cytokine storm syndromes

Since cytokine storm syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and coagulopathy, including those seen in COVID-19, are fatal, development of highly effective therapeutics is urgently needed. We previously reported that the hydrolysis of extracellular vesicles (EVs) by secreted phospholipase A2 (sPLA2) leads to production of immunomodulatory lipid mediators in lymphoproliferative diseases. We aimed to apply this phenomenon technically using sPLA2-reacted EVs — here in designated as “SPLEVs”, which showed high therapeutic efficacies against various disease. Mechanistically, SPLEVs bind to type II alveolar epithelial cells and elicit “lipid counterstorm”, drastically increasing the production of tissue-protective and anti-inflammatory lipid mediators through the phosphoinositide 3-kinase and sterol regulatory element-binding protein 1 pathways. And these effects showed an important role of PG in hep-EVs, and Lyso-PG hydrolyzed by sPLA2 was involved in the regulation of inflammation. Also, hep-SPLEVs injection showed increased lipid mediators and anti-inflammatory effects in inflammatory diseases other than ARDS, prolonged survival and reduced tissue damage. Thus, SPLEVs are expected to be an effective therapeutic tool for treatment of broad ranges of inflammatory diseases including COVID-19 and other new pandemic diseases.