Inflammatory bowel disease (IBD) is a chronic condition that’s often accompanied by mental comorbidities like anxiety and depression. While current treatments can help relieve some symptoms, the complex mechanisms behind these comorbidities highlight an urgent need for therapies that combine anti-inflammatory effects, barrier repair, and microbiome regulation. In this study, we developed a series of nanozyme-exoskeletal yeast-derived polysaccharides (NZEPs) by integrating nanozymes with yeast-derived polysaccharides, inspired by insect hardening strategies. Among them, NZEP TA-CE showed the highest level of nanozyme exoskeleton formation and could break the vicious cycle of inflammation by inhibiting MAPK- and NF-κB-mediated inflammatory signaling pathways. When administered orally to mice, NZEP TA-CE effectively targeted and accumulated in inflamed colon regions, restored intestinal inflammation balance, and promoted gut barrier repair. Additionally, NZEP TA-CE treatment could reverse gut microbiota imbalance and optimize microbial metabolite composition, helping relieve anxiety and depression symptoms linked to IBD. This study offers a safe and promising therapeutic strategy for managing IBD and its associated psychological comorbidities.

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DOI:10.1038/s41467-026-78633-3