Oral cascade–responsive nanomedicine to disrupt macrophage–neutrophil crosstalk for intestinal barrier repair

Intestinal barrier dysfunction underlies inflammatory bowel disease (IBD) and is driven, in part, by pathological crosstalk between macrophages and neutrophils that sustains pro-inflammatory cytokine release and excessive formation of neutrophil extracellular trap (NET). In this study, an oral cascade-responsive nanomedicine, PLBD, was developed to co-deliver the prostaglandin D₂ receptor agonist BW245C and the NET scavenger DNase I with precise spatiotemporal control and minimal off-target release. PLBD comprises mucus-penetrating, reactive oxygen species (ROS)-sensitive liposomes (LBD) formulated from DSPE-SeSe-PEG, which co-encapsulate BW245C and DNase I, and a microbiota-degradable pectin shell providing gastrointestinal protection. After oral administration, the pectin coating facilitates colonic accumulation and undergoes microbiota-mediated fermentation, whereas the exposed PEGylated liposomes penetrate the mucus barrier. In the ROS-rich inflammatory microenvironment, cleavage of the Se-Se linker triggers the synchronous release of payloads. Functionally, released BW245C facilitates a functional shift in macrophages toward an anti-inflammatory M2-like state while DNase I degrades dysregulated NETs, interrupting the inflammatory loop. In murine models of intestinal barrier dysfunction, PLBD restores epithelial barrier integrity, reduces bacterial translocation, rebalances gut microbiota, attenuates IBD and systemic inflammation. Together, this work validates macrophage-neutrophil crosstalk as a tractable therapeutic target and provide a safe, orally translatable biomaterials strategy for intestinal barrier repair.