Hydrogel‐Based Artificial Mucosa Restores Local Immune and Microbial Homeostasis for Treating Ulcerative Colitis

Abstract Ulcerative colitis (UC) is a common inflammatory bowel disease driven by the dyshomeostasis of intestinal immune system and microbiota, but its treatment options are limited due to impaired epithelial barrier integrity and function. Herein, a multifunctional biomimetic hydrogel is developed as artificial colonic mucosa, which can readily establish a bioadhesive barrier at the ulcer site and restore local immune and microbial homeostasis to exert potent anti‐inflammatory effect. The hydrogel framework is generated through the thrombin‐mediated activation and polymerization of fibrinogen that resembles natural blood coagulation mechanism. During this process, the antibacterial agent Ag⁺ is used for the crosslinking between the generated fibrin units and dopamine/thiol‐modified hyaluronic acid biopolymers via Ag⁺‐thiol coordination to convey enhanced bioadhesiveness, while the interconnected porous network is employed to encapsulate basic fibroblast growth factor (bFGF) and alanyl‐glutamine (ALG) for mucosa regeneration. The hydrogel stably adheres to the ulcer site to protect and repair the damaged epithelium and establishes an anti‐inflammatory microenvironment by inducing locoregional M1‐to‐M2 macrophage repolarization while eliminating harmful gut flora, which can act in a cooperative manner to substantially alleviate UC symptoms. The biomimetic hydrogel here presents a promising approach for effective UC therapy in the clinics.