Background Serum small extracellular vesicles (sEVs) and their small RNA (sRNA) cargoes could be promising biomarkers for the diagnosis of liver injury. However, the dynamic changes of serum sEVs and their sRNA components during liver injury and the biological functions of these liver-injury-serum sEVs have not been well characterized. Methods To identify serum sEV biomarkers for liver injury, we established a carbon tetrachloride-induced mouse liver injury model to simulate acute liver injury

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... ALI), chronic liver injury (CLI) and recovery. Serum sEVs were obtained and characterized. Serum sEV sRNAs were profiled. Differentially expressed microRNAs (miRNA) were compared to mouse liver enriched miRNAs and previously reported circulating miRNAs that related to human liver diseases. The biological significance was evaluated by Ingenuity Pathway Analysis of altered sEV miRNAs, and conditional culture of ALI serum sEVs with primary hepatic macrophages. Results We found that both ALI and CLI changed the concentration and morphology of serum sEVs. The proportion of serum sEV miRNA increased upon liver injury, with the liver as the primary contributor. The altered serum sEV miRNAs based on mice's study were consistent with those human liver diseases-related circulating miRNAs. Serum sEV miRNA signatures for ALI and CLI, and a panel of miRNAs as common marker for liver injury, were established. The differential serum sEV miRNAs in ALI mainly contributed to liver steatosis and inflammation, while those in CLI primarily contributed to hepatocellular carcinoma and hyperplasia. ALI serum sEVs decreased both CD86 and CD206 expression in monocyte-derived macrophages, but increased CD206 expression in resident macrophages. Conclusion Serum sEVs in the different stages of liver injury carried different sRNA messages and contributed to diverse pathological processes. ALI serum sEVs might alleviate liver damage by depolarizing monocyte-derived macrophages and educating resident liver macrophage to M2 like cells.