Host-derived membranes can confer disguise against host defense arsenals and greatly facilitate viral exploitation of host cell resources for rapid, unsupervised viral multiplication (Cosset and Dreux, 2014). Indeed, RNA viruses had hitherto been discovered to hijack the exosomal pathway, which normally mediates endogenous intercellular communication, for viral assembly, transmission, and suppression of immune activation (Chahar et al., 2015). Our comprehensive, quantitative analyses of serum lipidome and metabolome in COVID-19 patients and healthy controls revealed that the overall serum lipidomic signatures associated with COVID-19 closely mirrored that of exosomal membrane lipid composition, which comprises enhanced levels of SMs and GM3s (cell-type specific) and reduced amounts of DAGs (Subra et al., 2007), indicating GM3-enriched exosomes might be associated with the pathogenesis of COVID-19. We validated our postulations drawn based on plasma lipidomes using exosomes isolated from the same cohort and demonstrated that exosomes were increasingly enriched in GM3s with elevating disease severity of COVID-19. As GM3s were the only pathologically altered plasma lipids that were negatively correlated with T cell counts and CD4+ T cell counts in COVID-19 patients, we postulate that GM3-enriched exosomes might participate in pathological processes that target CD4+ T cells. Indeed, GD3 gangliosides on the surface of exosomes isolated from fluids of ovarian tumor ascites were causally associated with the functional arrest of T cells, contributing to an immunosuppressive tumor microenvironment. Furthermore, removal of sialic motifs from GD3-coated exosomes obliterated their inhibitory capacity on T cells (Shenoy et al., 2018).