This study investigates the therapeutic potential of exosomes derived from lipopolysaccharide (LPS)-preconditioned mesenchymal stem cells (MSCs) in treating sepsis. The research demonstrates that these exosomes significantly reduce inflammation, improve survival rates, and enhance M2 macrophage polarization in septic mice. The exosomes were found to carry miR-150-5p, which targets Irs1 and modulates the PI3K/Akt/mTOR pathway, thereby promoting macrophage polarization and reducing sepsis-induced damage. The study highlights the potential of exosomes as a cell-free therapeutic approach for sepsis, with miR-150-5p identified as a novel molecular target for regulating immune hyperactivation during sepsis. The findings suggest that LPS preconditioning of MSCs enhances the therapeutic efficacy of exosomes, making them a promising strategy for sepsis treatment. The study also provides insights into the molecular mechanisms underlying the anti-inflammatory effects of exosomes, including their role in modulating macrophage polarization and immune responses. Overall, the research underscores the importance of exosomes in sepsis treatment and identifies miR-150-5p as a key regulatory factor in the immune response to sepsis.This study investigates the therapeutic potential of exosomes derived from lipopolysaccharide (LPS)-preconditioned mesenchymal stem cells (MSCs) in treating sepsis. The research demonstrates that these exosomes significantly reduce inflammation, improve survival rates, and enhance M2 macrophage polarization in septic mice. The exosomes were found to carry miR-150-5p, which targets Irs1 and modulates the PI3K/Akt/mTOR pathway, thereby promoting macrophage polarization and reducing sepsis-induced damage. The study highlights the potential of exosomes as a cell-free therapeutic approach for sepsis, with miR-150-5p identified as a novel molecular target for regulating immune hyperactivation during sepsis. The findings suggest that LPS preconditioning of MSCs enhances the therapeutic efficacy of exosomes, making them a promising strategy for sepsis treatment. The study also provides insights into the molecular mechanisms underlying the anti-inflammatory effects of exosomes, including their role in modulating macrophage polarization and immune responses. Overall, the research underscores the importance of exosomes in sepsis treatment and identifies miR-150-5p as a key regulatory factor in the immune response to sepsis.