Prior exposure to lipopolysaccharides (LPS) induces host reprogram state of repressing inflammatory responses, however, the molecular mechanisms remain elusive.Exosomes play a pivotal role in cell-to-cell communication and exert regulatory function by carrying bioactive molecules.Recent reports have suggested that the immunomodulatory activity of mesenchymal stem cells (MSCs) is mediated through the release of exosomes.Here, we showed, after appropriate LPS stimulated, MSCs didn't display any observable phenotype change and can release plenty of exosomes around 60 nm in diameter.In vitro, LPS preconditioning MSCs derived exosomes (LPS-exosomes) have a better ability to modulate the balance of macrophages through upregulating the expression of anti-inflammatory cytokines and promoting M2 macrophages activation than untreated MSCs derived exosomes (un-exosomes).Microarray analysis of LPS-exosomes identified that unique expression of let-7b compared with un-exosomes, and the let-7b/TLR4 pathway served as potential contributor for macrophage polarization and inflammatory ablation.Transfection of LPS-exosomes treated THP-1 cell with let-7b mimics increased M2 marker Arg-1, while let-7b inhibitor increased M1 marker iNOS.Further investigation of mechanisms that control let-7b expression demonstrated that a TLR4/NF-KB/STAT3/AKT regulatory feedback loop plays a vital role in the regulation of macrophage plasticity.Knockdown of AKT in THP-1 cell similarly abolished the immunomodulatory effect of LPS-exosomes.Thus, our results suggest that LPS-exosomes may contribute to the resolution of inflammation by transferring let-7b and carry much immunotherapeutic potential for the inflammation-related diseases.