Exosomal dsDNA promoted intestinal inflammation via activating the STING pathway in macrophages.Elevated dsDNA levels in EVs of plasma were found in active CD patients and DSS-induced mice. Phosphorylated STING and p-IRF3 proteins were increased in the colon tissues and macrophages of active CD patients. Also, EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. Blockade of EVs by intraperitoneal injection of GW4869 ameliorated murine colitis by inhibiting the activation of the STING pathway. Here, IRF3 is linked to colitis.