SpyTag-PEGylated probiotics delivering IL-1Ra modulate gut-lung crosstalk to mitigate septic lung injury.

Mortality resulting from sepsis is highly associated with secondary acute lung injury, and although the gut-lung axis is of significant importance, treatment strategies leveraging this understanding remains limited. Here, we developed an Escherichia coli strain named ΔPESI that highly expresses IL-1Ra via outer membrane vesicles (OMVs) and PEGylated this strain through the SpyCatcher-SpyTag system for enhanced activity and colonization. Oral administration of ΔPESI reinforces epithelial barrier integrity in the gut, inhibits inflammatory cascade in the peripheral circulation, modulates macrophage polarization and pyroptosis in the lung, thereby significantly mitigating the dysregulated systemic inflammatory response. Furthermore, ΔPESI exhibits favorable biosafety characteristics, thus demonstrating strong potential for clinical translation. Hence, this study proposes a promising strategy for the oral administration of engineered probiotics to effectively alleviate intestinal and pulmonary inflammatory responses through modulation of the gut-lung crosstalk.