To summarize, our extensive lipidomics and metabolomics analyses of plasma changes associated with COVID-19, in combination with differential correlation network analyses for systems metabolic pathway interrogation, provided evidence that implicated GM3-enriched exosomes in COVID-19 pathogenesis. We validated our postulations drawn based on plasma lipidomes by analyzing lipid changes in isolated exosomes, which demonstrated that exosomes were increasingly enriched in GM3s with elevating disease severity in COVID-19.