Systemic Inflammation Modulates Clearance and Drives Extra‐Hepatic Distribution of Extracellular Vesicles

Extracellular vesicles (EVs) are promising vehicles for targeted therapeutic delivery, capable of encapsulating and transporting biomolecules to specific cells and tissues. Given that inflammation is central to many acute and chronic diseases, understanding EV biodistribution under inflammatory conditions is essential for therapeutic optimisation. This study examines how acute systemic inflammation influences EV biodistribution, clearance and plasma half-life, with a focus on the role of macrophages and their polarisation states. Using a lipopolysaccharide (LPS)-induced inflammation model in wild-type mice and bioluminescent and fluorescent labelling of EVs, we observed that inflammation extends the plasma half-life of EVs by over 600-fold within 2 h and 900-fold at 24 h post-administration, leading to significant enrichment in inflamed organs, particularly the liver and spleen. Enhanced accumulation in specific tissues translated to increased targeting of immune- and epithelial cells within those organs, with notable uptake by hepatocytes in the liver. To probe the mechanism, we profiled the EV protein corona, revealing inflammation-driven remodelling with enrichment of acute-phase proteins, complement factors and cytoskeletal regulators-linking corona composition to altered biodistribution. Yet, despite increased uptake and tissue accumulation, functional EV cargo delivery in vivo remained limited. These findings underscore the complex dynamics between EVs and immune cells under inflammatory conditions and provide critical insights for advancing EV-based therapies in chronic inflammatory diseases.