Adjunctive treatment of sepsis with mesenchymal stem cell-derived extracellular vesicles: a systemic review and meta-analysis of pre-clinical studies

Abstract Background: Multiple preclinical studies have reported a beneficial effect of extracellular vesicles (EVs), especially mesenchymal stem cell-derived EVs (MSC-EVs), in the treatment of sepsis. However, the therapeutic effect of MSC-EVs is still unclear. Therefore, we conducted this meta-analysis by summarizing data from all published studies that met the criteria for a systematic review on the association between EV treatment and mortality in animal models of sepsis. Methods: Systematic retrieval of all studies in PubMed, Scopus, and Web of Science that reported the effects of EVs on sepsis models up to December 2023 was performed. The targeted outcome was animal mortality. After screening the eligible articles according to inclusion and exclusion criteria, the inverse variance method of the fixed effect model was used to calculate the joint odds ratio (OR) and 95% confidence interval (CI). Results: A total of 53 studies met the inclusion criteria, indicating that EVs treatment was associated with reduced mortality in animal models of sepsis, with a RR of 0.53 and a 95%CI of 0.46 to 0.60 (p < 0.001) and RD of -0.35 and 95%CI of -0.41 to -0.30 (p < 0.001). Subsequent subgroup analysis revealed that several factors,such as sepsis models and EV administration (source, dose, time to injection, and route of administion), may significantly affect the therapeutic efficacy of EVs. Conclusion: This meta-analysis showed that MSC-EVs treatment may be associated with lower mortality in animal models of sepsis. Subsequent preclinical studies will need to address the standardization of dose, source, and timing of EVs to provide comparable data. In addition, the effectiveness of EVs in treating sepsis must be studied in large animal studies to provide important clues for human clinical trials.