Layer-by-layer engineered outer membrane vesicles enable oral upadacitinib delivery for inflammation control and fibrosis attenuation in ulcerative colitis.

Ulcerative colitis (UC) is characterized by intertwined defects in the epithelial barrier, microbiota composition, and immune signaling, which collectively sustain inflammation and drive fibrosis. Here, we report a multifunctional oral nanoplatform OMV-LbL@Upa (OUL), comprising probiotic-derived outer membrane vesicles (OMVs) encapsulating the JAK-STAT inhibitor upadacitinib (Upa), further functionalized with a trans-cinnamic acid/chitosan-based layer-by-layer (LbL) coating. The LbL architecture significantly enhanced gastric stability and intestinal retention, enabling colon-targeted release while preserving OMV bioactivity. In both acute and chronic UC models, OUL significantly improved disease activity, restored tight junction proteins, corrected intestinal permeability, rebalanced gut microbiota, and reprogrammed macrophage polarization. Mechanistically, OUL suppressed JAK-STAT signaling pathways, culminating in attenuated collagen deposition and the downregulation of pro-fibrotic markers (α-SMA and vimentin). With no overt systemic toxicity observed, this orally administered nanoplatform integrates microbiota/epithelial restoration with targeted JAK1 inhibition to achieve anti-inflammatory and anti-fibrotic benefits, offering a clinically promising strategy for the management of UC.