Orally deliverable Perilla frutescens-derived nanovesicles as natural bioactive nanocarriers for colon-targeted colitis therapy via microenvironment reprogramming.

Effective oral therapy for inflammatory bowel disease (IBD) requires overcoming gastrointestinal barriers to modulate the dysregulated mucosal niche. Here, we present edible nanovesicles derived from Perilla frutescens (PLENs) as an intrinsically stable, bioactive nanotherapeutic. Multi-omics profiling defined a robust lipid-bilayer architecture encapsulating a synergistic cargo of proteins, miRNAs, and antioxidant metabolites. This structural integrity enabled PLENs to survive gastrointestinal transit and exhibit preferential fluorescence localization with prolonged retention in the inflamed colonic region, as indicated by in vivo imaging. Upon localization, PLENs executed a "dual-hit" therapeutic strategy: they reprogrammed the immune microenvironment, accompanied by reduced activation of the TLR4/MyD88-NF-κB axis and a phenotypic shift from pro-inflammatory M1 to reparative M2 macrophages. Concurrently, PLENs fundamentally restructured the gut ecosystem, accompanied by enrichment of taxa linked to saccharolytic fermentation and recovery of cecal short-chain fatty acids. Notably, fecal microbiota transplantation (FMT) further supported that this microbial remodeling contributed to the protective phenotype, highlighting the microbiome as an important component of efficacy.