Lotus-derived protein-rich nanoparticles relieve inflammatory bowel disease by modulating gut microbiota and bile acid metabolism.

Plant-derived nanovesicles (PDNs) enriched with diverse bioactive constituents, including proteins, lipids, and RNAs, which possess a wide range of biological activities. PDNs exhibit therapeutic potential for the oral treatment of inflammatory bowel disease (IBD). However, the roles of PDNs derived from lotus roots on IBD remain unclear. Herein, we extracted and purified nanovesicles derived from lotus root (LDNs), which displayed a typical "cup-shaped" morphology and an average diameter of 82.9 nm. LDNs primarily contain functional proteins, with 71 proteins identified. In vitro studies demonstrated that protein-rich LDNs were preferentially internalized within 6 h and exhibited anti-inflammatory activity in lipopolysaccharide (LPS)-challenged NCM460 cells. In vivo experiments revealed that LDNs were primarily enriched in the gastrointestinal tract following oral administration. In dextran sulfate sodium-induced IBD mice, LDNs effectively restored colon length, reduced the inflammatory response, and ameliorated damage to the intestinal tract. Mechanistically, LDNs modulated the tight junctions (TJs) pathway to restore intestinal barrier function while also reducing inflammation. Additionally, LDNs alleviated DSS-induced gut microbiota dysbiosis and abnormal bile acid metabolism by reshaping gut microbiota. Our findings indicate LDNs, as an oral natural nanomedicine, could serve as a promising alternative therapy for treating IBD, with distinct efficacy and mechanism.