miR166u -enriched Polygonatum sibiricum exosome-like nanoparticles alleviate colitis by improving intestinal barrier...

Polygonatum sibiricum-derived exosome-like nanoparticles (PSELNs) have emerged as promising natural nanocarriers for modulating intestinal inflammation, yet their therapeutic mechanisms remain unclear. This study evaluates the protective effects and underlying pathways of PSELNs against dextran sulfate sodium (DSS)-induced colitis in mice. PSELNs were isolated from P. sibiricum rhizomes using tangential flow filtration and characterized via transmission electron microscopy, nanoparticle tracking analysis, and miRNA sequencing. Oral administration of PSELNs demonstrated notable gastrointestinal stability and targeted colon delivery in vivo. In the DSS-induced colitis model, PSELNs significantly ameliorated disease severity, restored colonic histological architecture, and enhanced intestinal barrier integrity by upregulating tight junction proteins (ZO-1, Occludin) and mucin (MUC2) expression. PSELNs also attenuated inflammation by reducing TNF-α and LPS levels and downregulating TLR4/AKT/NF-κB signaling, as confirmed byRT- qPCR and Western blot analyses. 16S rRNA sequencing and untargeted metabolomics revealed that PSELNs reshaped gut microbiota composition-particularly increasing Akkermansia-and modulated amino acid and steroid metabolism. Mechanistically, the highly abundant miR166u in PSELNs directly targeted CD11c, thereby suppressing downstream pro-inflammatory signaling. These findings highlight PSELNs as a novel dietary-derived therapeutic strategy to alleviate colitis via gut barrier restoration, immune modulation, and microbiota-metabolite interactions.