Polysaccharide Engineered Nanozymes Target Inflammation for Alleviating Colitis‐Associated Mental Disorders via Microbiome‐Gut–Brain Axis

ABSTRACT Molecular therapies for colitis‐associated mental disorders show limited efficacy because they usually focus on a single pathway and exhibit substantial off‐target toxicity toward healthy tissues. To tackle this limitation, bioinformatic approaches are employed to predict that inflammation and metabolism may be potential targets for Fucoidan. Guided by this prediction, we develop oral polysaccharide engineered nanozymes, Fucoidan‐cerium nanocomplexes (FucCeNCs), which are capable of targeting the inflamed colon through electrostatic interactions, exerting anti‐inflammatory effects, and concurrently regulating gut microbiota‐derived metabolism. In a murine model of ulcerative colitis‐associated mental disorders, FucCeNCs show anti‐inflammatory and gut barrier‐protective effects, thereby suppressing microglial/astrocytic overactivation and preserving neuronal integrity through the transmission of anti‐inflammatory cytokines via gut–brain axis. Importantly, FucCeNCs restore gut microbial homeostasis through increasing the relative abundance of probiotics and reducing proportions of pathogens. This shift results in a marked attenuation of abnormal amino acid biosynthesis and metabolism in fecal metabolites, which in turn leads to elevated levels of bioactive metabolites such as homovanillic acid and γ‐aminobutyric acid. These metabolites ultimately attenuate neuroinflammation via the microbiome‐gut–brain axis, ameliorating depression‐ and anxiety‐like behaviors. These results identify microbiome‐gut–brain axis as pivotal therapeutic target for colitis‐associated mental disorders therapy, which can be addressed by polysaccharide engineered nanozymes.