Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cellâbased therapies. However, the efficacy and underlying mechanisms of EVâbased treatment in hepatic ischemiaâreperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSCâEVs (hucâMSCâEVs) could protect against IRIâinduced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, hucâMSCâEVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stressâinduced cell death in vitro. Interestingly, we found that the mitochondriaâlocated antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in hucâMSCâEVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in hucâMSCs decreased the level of MnSOD in hucâMSCâEVs and attenuated the antiapoptotic and antioxidant capacities of hucâMSCâEVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20âtetrakis (4âbenzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of hucâMSCâEVs on hepatic IRI and evaluate their preclinical application.âYao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemiaâreperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695â1710 (2019). http://www.fasebj.org