Oral multilayer nanomedicine for gut barrier repair and immune–microbiota reprogramming in inflammatory bowel disease and inflammatory arthritis

Inflammatory bowel disease (IBD) emerges from a self-reinforcing triad of epithelial barrier failure, oxidative stress, and immune dysregulation, while concomitants dysbiosis amplifies mucosal inflammation and— via the gut–joint axis—drives systemic autoimmunity such as rheumatoid arthritis (RA). Here, we report a triple-action multilayer oral nanoplatform, LBL-BM, that co-delivers berberine (BBR), myricetin (MYR), and TNF- α -targeting small interfering RNA (siTNF- α ). A chitosan/siTNF- α /alginate shell over a supramolecular BBR/MYR core overcomes gastrointestinal instability, poor lesion targeting, and fleeting siRNA exposure, enabling redox control and epithelial support coupled with pro-inflammatory cytokine silencing. This platform reduces reactive oxygen species (ROS), attenuates oxidative injury and apoptosis, and preserves tight-junction proteins. In dextran sulfate sodium (DSS)-induced colitis, it significantly improves clinical and histological outcomes, skews macrophage polarization toward an M2 phenotype, and reprograms the microbiota toward short-chain fatty acids (SCFAs)-associated, inflammation-attenuating communities. Consistent with modulation of the gut–joint axis, benefits extended beyond the intestine: in collagen antibody-induced arthritis (CAIA) it lowers clinical scores and paw swelling, attenuates synovitis and bone erosion, preserves cartilage, and reduces systemic cytokines (TNF- α , IL-17A, and IL-1 β ). Collectively, these findings establish LBL-BM as a multifunctional oral nanomedicine that restores intestinal homeostasis and holds translational promise for treating both IBD and RA.