Extremophyte-derived exosome-like nanovesicles remodel intestinal barrier dysfunction by multi-dimensional intervention: physical barrier repair with immune homeostasis and microbiome regulation.

Intestinal barrier is the body's largest immune structure and essential for nutrient absorption. Its dysfunction allows the translocation of pathogenic substances into circulation, thereby driving the pathogenesis of inflammatory bowel disease (IBD). Plant-derived exosome-like nanovesicles (ELNs), recognized for their biocompatibility and ability to traverse biological barriers, hold considerable potential for managing intestinal inflammation. Specially, plants cultivated under extreme environmental conditions typically adapt to be stress resistant with greater accumulation of associated biologics, which may in-turn confer unique bioactivities to their respective ELNs. This study investigated the protective effects and mechanisms of ELNs derived from the extremophyte Rosa roxburghii (R-ELNs) and Artemisia sphaerocephala Krasch (A-ELNs) against intestinal barrier dysfunction. In vitro and in vivo studies indicated that the ELNs, especially R-ELNs, provided enhanced protection against intestinal barrier dysfunction. Specifically, mucus secretion and tight junction protein expression were promoted, and macrophages were polarized toward M2 anti-inflammatory phenotypes. Furthermore, R-ELNs modulated the composition of the intestinal microbiota, thereby promoting a balanced microecological environment. Importantly, the protective effect of R-ELNs was suggested to be through an inhibitory effect on excessive activation of pro-inflammatory signaling proteins (AKT, p38). Notably, exosomes (Exos) derived from R-ELN-treated M2 macrophages had distinct miRNA profiles that can target inflammatory pathway genes (Tgfbr1, Map3k7, Met), enabling anti-inflammatory roles via intercellular communication. These findings suggested that R-ELNs can restore intestinal barrier dysfunction via multiple synergistic mechanisms, positioning R-ELNs as a novel and promising preventive strategy for inflammatory bowel disease.