Small extracellular vesicles from DENV2-infected C6/36 cells show viral infection <i>in vitro</i> and <i>in vivo</i>

Dengue, transmitted by <i>Aedes</i> mosquitoes, can progress to severe symptoms like hemorrhagic fever and shock syndrome. While the virus and host immune response contribute to severity, other factors, such as small extracellular vesicles (sEVs), may play a role. sEVs mediate intercellular communication by transferring cellular components; however, their role <i>in vivo</i> infection remains unclear. We isolated and characterized sEVs from DENV-infected C6/36 mosquito cells, finding that they interact with mammalian cells and internalize the content. Using sEVs populations (with a size between 100 and 200 nm), we demonstrated enhanced infection in <i>in vitro</i> and <i>in vivo</i> murine models, including immunocompetent and immunosuppressed mice, which developed severe dengue-like symptoms. Our study reveals that sEVs from DENV-infected mosquito cells contribute to dengue pathogenesis, inducing severe symptoms in <i>in vivo</i> models, highlighting their potential role in disease progression and severe outcomes.