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Figure 1. Potential role of EVs in COVID-19 disease pathogenesis and therapeutics. SARS-CoV-2 virions enter the host via the large airways and can travel into alveoli where they infect type II pneumocytes. Infection of type II pneumocytes by SARS-CoV-2 induces a proinflammatory response that activates alveolar macrophages and damages the alveolar epithelium. It is speculated that EV crosstalk between alveolar macrophages and alveolar epithelial cells could intensify inflammation and further enhance alveolar epithelial permeability. This may lead to increased permeability of the alveolar-capillary barrier, causing pulmonary edema and decreased functional capacity of the lungs, thereby allowing SARS-CoV-2 virions, EVs, and other inflammatory mediators to enter the bloodstream and progress to systemic infection. SARS-CoV-2 virions in the blood are suggested to infect endothelial cells and cause endothelial dysfunction, which ultimately leads to blood clots that can cause major thrombotic events as well as activation of circulating immune cells. On the contrary, engineered EVs could also be used as a therapeutic tool against COVID-19. EVs modified to express ACE2 may be injected into the bloodstream or nebulized and could potentially prevent SARS-CoV-2 from infecting healthy cells in either the bloodstream or alveolar space. These ACE2-expressing EVs may also be taken up by endothelial cells, increasing the amount of surface ACE2 expression on these cells, and maintaining the appropriate function of RAAS. In addition, injected MSC-EVs have anti-inflammatory properties that can promote tissue repair and prevent hyperinflammation during SARS-CoV-2 infection and ARDS. In COVID-19, they might be particularly useful for decreasing endothelial damage and preventing immune activation. (The copyright is retained by the authors).