FGF21-loaded M2 macrophage-derived exosomes attenuate sepsis-induced lung injury by regulating M2 macrophage polarization and glycolysis.

Sepsis, a critical lethal critical illness, involves glucose and lipid metabolism disorders. However, the specific mechanisms underlying these alterations require further investigation. Acute lung injury (ALI), one of the most serious complications of sepsis, has a high mortality rate. Fibroblast growth factor 21 (FGF21), a key metabolic regulator, can regulate glucose metabolism. However, the short half-life (t½) of FGF21 limits its clinical application. In this study, we designed FGF21-loaded M2 macrophage-derived exosomes, named FGF21-M2-Exos, for the treatment of sepsis-induced ALI. We demonstrated that FGF21-M2-Exos were able to release FGF21 in a controlled and sustained manner. In addition, FGF21-M2-Exos were present in the lungs of mice at 24 h. Importantly, our results suggest that FGF21-M2-Exos alleviate sepsis-induced lung damage. Moreover, the RNA sequencing results revealed that FGF21-M2-Exos regulate immune function via several inflammatory signalling pathways. Furthermore, we found that FGF21-M2-Exo administration protects against sepsis-induced lung injury by downregulating inflammation-related protein expression, promoting M2 macrophage polarization, inhibiting glycolysis and reducing cellular apoptosis. Overall, the use of FGF21-M2-Exos, which regulate inflammatory and metabolic processes, may be a promising strategy for treating sepsis-induced ALI.