A Natural Self‐Assembled Hydrogel Alleviates Inflammatory Bowel Disease by Targeting Mitochondrial Dysfunction and NLRP3/Caspase‐1/GSDMD‐Mediated Pyroptosis

ABSTRACT Oxidative stress‐induced mitochondrial damage and NLRP3/Caspase‐1/GSDMD‐mediated pyroptosis are pivotal pathological mechanisms in inflammatory bowel disease (IBD), which are often exacerbated by gut microbial dysbiosis. In this study, we designed and fabricated a carrier‐free GMR hydrogel via Mg 2+ ‐mediated self‐assembly of natural products glycyrrhizic acid (GA) and rosmarinic acid (RA) for the treatment of IBD. In established models of ulcerative colitis (UC) and Crohn's disease (CD), GMR hydrogel exhibited remarkable protective and therapeutic effects. Its efficacy is achieved through a dual mechanism: protecting intestinal epithelial cells (IECs) via ROS elimination and mitochondrial preservation, and mitigating pyroptosis by modulating the NLRP3/Caspase‐1/GSDMD pathway, which collectively led to reduced IL‐1β and IL‐18 levels. Consequently, GMR hydrogel elicited comprehensive therapeutic effects, including the restoration of intestinal barrier integrity via upregulation of tight junction proteins (ZO‐1, occludin, and claudin‐1) and the remodeling of gut microbiota to enhance diversity and short‐chain fatty acids (SCFAs) production. These improvements collectively created an anti‐inflammatory microenvironment that ameliorated IBD symptoms. Collectively, these findings demonstrate that the multi‐component self‐assembled GMR hydrogel targets the core pathological pathways of mitochondrial damage and pyroptosis in IBD to restore intestinal homeostasis, positioning this biocompatible platform as a highly promising therapeutic strategy.