Bioinspired nanozyme-exoskeletonized yeast-derived polysaccharides for treating comorbid anxiety and depression in inflammatory bowel disease

Abstract Inflammatory bowel disease (IBD) is a chronic condition frequently accompanied by psychological comorbidities, such as anxiety and depression. Although current treatments may alleviate some of these symptoms, the intricate pathogenesis of these comorbidities highlights an urgent need for therapeutic strategies with combined anti-inflammatory, barrier-reparative, and microbiota-modulating effects. Herein, we develop a series of nanozyme-exoskeletonized yeast-derived polysaccharides (NZEP) by integrating nanozymes with yeast-derived polysaccharides using an insect sclerotization-inspired strategy. Among them, NZEP TA-Ce , with the highest degree of nanozyme-exoskeletonization, is capable of disrupting the inflammatory vicious cycle by inhibiting MAPK and NF-κB-mediated inflammatory signaling pathways. Oral administration of NZEP TA-Ce in mice enables effective retention and accumulation in inflamed colonic regions, reverses the homeostasis imbalance of intestinal inflammation and promotes intestinal barrier repair. Furthermore, NZEP TA-Ce treatment reverses gut microbiota dysbiosis and optimizes the composition of microbial metabolites, thereby alleviating anxiety and depressive symptoms associated with IBD. This study provides a safe and promising therapeutic strategy for the management of IBD patients and their associated psychological comorbidities.