A relevant part of the physiological functions of extracellular vesicles is conditioned by the protein corona attached to the surface. The composition of this corona is initially defined during their intracellular synthesis, but it can be modified subsequently by the interactions with the microenvironment. Here we evaluated how the corona of small extracellular vesicles exposed to the inflammatory environment generated in acute pancreatitis is modified and which functional changes their undergo as a result of these modifications. Small extracellular vesicles obtained from a pancreatic cell line were incubated with the ascitic fluid generated in experimental acute pancreatitis in rats. By proteomic techniques, we have detected the appearance of new proteins and the redistribution of some others already present. These changes increase the uptake of extracellular vesicles by some cell types and the response induced in inflammatory cells. The inhibition of different Pattern recognition receptors reversed this activation, indicating that some of these effects could be due to binding of Damage-associated molecular patterns to the corona. All this indicates that in pathologies such as acute pancreatitis, with an inflammatory response and intense tissue damage, the microenvironment substantially modifies the corona of extracellular vesicles, thus altering their behavior and enhancing their inflammatory activity.