Hierarchical surface engineering of probiotics for enhanced intestinal retention and colitis therapy

Inflammatory bowel disease (IBD) is characterized by a hostile intestinal microenvironment involving excessive oxidative stress, epithelial barrier disruption, and gut microbiota dysbiosis. However, effective strategies for achieving sustained mucosal healing and long-term remission remain limited. Here, we report a dual-layer engineered probiotic (designed as EcN@PDA@MPN) via a two-step one-pot surface engineering strategy that sequentially integrates a polydopamine (PDA) layer and zinc-tannic acid metal-phenolic networks (MPN) onto Escherichia coli Nissle 1917. The inner PDA layer provides a biocompatible adhesive scaffold that stabilizes the bacterial surface and facilitates subsequent interfacial assembly, while the outer MPN shell offers dense, stimuli-responsive shielding against harsh gastrointestinal conditions and enables controlled release of bioactive zinc ions. This composite coating markedly enhances probiotic stability against gastric acid, digestive enzymes, and inflammatory oxidative stress, while preserving bacterial viability. In the dextran sulfate sodium-induced murine colitis model, oral administration of EcN@PDA@MPN significantly alleviated disease severity, as evidenced by reduced weight loss, preservation of colon length, and improved histopathological outcomes. Mechanistically, transcriptomic and microbiome analyses revealed that EcN@PDA@MPN exerts a triple therapeutic action, including suppressing pro-inflammatory signaling pathways and cytokines, restoring intestinal epithelial barrier integrity via upregulation of tight-junction proteins, and reshaping gut microbiota composition by enriching beneficial commensals while inhibiting pathobionts. In addition, EcN@PDA@MPN exhibited enhanced intestinal retention and preferential accumulation in inflamed colonic regions with no observable systemic toxicity. This work establishes a probiotic engineering paradigm that integrates protection, targeting, and microenvironment modulation for IBD treatment.