Multifunctional Zinc Glycyrrhizinate‐Integrated Gel for Enhanced Probiotic Delivery and Alleviation of Acute and Spontaneous Colitis
ABSTRACT Effective probiotic therapy for colitis is hindered by the harsh gastrointestinal (GI) physiologic and pathologic environment, including acidic pH, bile salts, elevated reactive oxygen species (ROS), mucus depletion, and dysbiosis. To address these challenges, we developed a novel “drug carrier‐integrated” oral probiotic delivery system—L. reuteri@ZGM—based on a zinc glycyrrhizinate microgel (ZGM) derived from the clinical anti‐inflammatory agent Licorzinc. This multifunctional gel encapsulates L. reuteri within a porous network, achieving a 23.08‐fold increase in survival rate under simulated gastric conditions and a 37.22‐fold increase in intestinal colonization in mice compared to unencapsulated bacteria. Beyond protection, ZGM actively scavenges ROS at inflammatory sites, facilitates probiotic adhesion to the mucus layer, and modulates the local microenvironment to favor colonization. In both dextran sulfate sodium (DSS)‐induced colitis and IL‐10‐deficient spontaneous colitis mouse models, L. reuteri@ZGM persistently scavenged ROS, effectively reduced pro‐inflammatory cytokine levels, restored the expression of tight junction‐associated proteins and intestinal barrier function, enhanced probiotic colonization and survival, and reshaped the gut microbiota. These findings establish L. reuteri@ZGM as a potent therapeutic strategy that integrates microenvironment modulation and probiotic delivery—offering a clinically translatable approach to treating inflammatory bowel diseases.