This study investigates the role of extracellular vesicles (EVs) in triggering systemic inflammation by examining their impact on cellular responses to inflammatory signaling. EVs, which transfer bioactive molecules between cells, are found to make non-responsive cells susceptible to inflammatory signals, leading to increased NF-κB activation and the release of inflammatory mediators. The study highlights the importance of Syntaxin-binding protein 1 (STXBP1) in the fusion process and the transfer of functionally active receptors from EVs to target cells. In vitro and in vivo experiments demonstrate that EVs can induce inflammatory responses without requiring further stimulation, and that receptor antagonists are ineffective in inhibiting NF-κB activation. However, blocking EV-EV fusion with heparin mitigates inflammation in mice challenged with EVs. The study also identifies a panel of signaling proteins in EVs from patients with polytrauma and sepsis, suggesting that EVs play a crucial role in severe inflammatory diseases. These findings provide insights into the molecular mechanisms underlying EV-induced inflammation and suggest potential therapeutic targets for anti-inflammatory and anticoagulant therapies.This study investigates the role of extracellular vesicles (EVs) in triggering systemic inflammation by examining their impact on cellular responses to inflammatory signaling. EVs, which transfer bioactive molecules between cells, are found to make non-responsive cells susceptible to inflammatory signals, leading to increased NF-κB activation and the release of inflammatory mediators. The study highlights the importance of Syntaxin-binding protein 1 (STXBP1) in the fusion process and the transfer of functionally active receptors from EVs to target cells. In vitro and in vivo experiments demonstrate that EVs can induce inflammatory responses without requiring further stimulation, and that receptor antagonists are ineffective in inhibiting NF-κB activation. However, blocking EV-EV fusion with heparin mitigates inflammation in mice challenged with EVs. The study also identifies a panel of signaling proteins in EVs from patients with polytrauma and sepsis, suggesting that EVs play a crucial role in severe inflammatory diseases. These findings provide insights into the molecular mechanisms underlying EV-induced inflammation and suggest potential therapeutic targets for anti-inflammatory and anticoagulant therapies.