Polysaccharide-functionalized metal-polyphenol network-coated porous microspheres for improving the treatment of probiotics in ulcerative colitis.

Probiotic therapy offers a new approach to the treatment of ulcerative colitis (UC), but oral drug delivery still faces challenges such as low gastrointestinal survival rates, insufficient intestinal retention, and poor inflammatory targeting. In this study, a layer-by-layer encapsulation probiotic delivery system (HGM-L.re PM) was developed. Lactobacillus reuteri (L.re) was loaded onto poly-L-lactic acid porous microspheres, followed by in situ assembly of a tea polyphenol/Fe3+ metal-polyphenol network (MPN) coating, and then layer-by-layer electrostatic deposition of an ethylene glycol chitosan/ hyaluronate (GCS/HA) polysaccharide gel layers via electrostatic interactions. The porous microspheres provide efficient probiotic loading and physical protection; the MPN coating confers transferrin-responsive degradability, enabling on-demand release at sites of inflammation; the GCS/HA outer layer synergistically forms a dense gel network via acid-triggered electrostatic cross-linking to resist gastric erosion, while the terminal HA moiety specifically binds to CD44 to enhance colonic adhesion. Compared to unencapsulated probiotics, HGM-L.re PM demonstrated significantly enhanced viability protection throughout all simulated stages of gastrointestinal digestion and achieved retention for up to 72 h in mice with colitis. In a DSS-induced acute UC model, this formulation effectively alleviated weight loss and colonic shortening, reduced mucosal damage, downregulated IL-6, IL-1β, and TNF-α levels, upregulated IL-10, restored the expression of mucin and tight junction proteins, and reshaped the gut microbiota composition by enriching beneficial bacteria such as Lactobacillus species. The underlying mechanism involves metabolic reorientation and stress resolution. The formulation also demonstrated good in vivo safety. This layer-by-layer encapsulated probiotic delivery platform offers a new strategy for enhancing the efficacy of oral probiotic therapy for UC.