Targeted β‐Glucan‐Veiled Oral Apremilast Nanotherapy Modulates Key Dysbiosis‐Associated Gut Microbiota and Alleviates Ulcerative Colitis‐Associated Anxiety, Depression, and Neuropsychiatric Behaviors

ABSTRACT Oral nanomedicines that modulate gut microbiota and gut–brain interactions are crucial for effectively treating inflammatory bowel disease (IBD) and associated psychiatric disorders, such as anxiety and depression. However, the underlying causes of psychiatric disorders in patients with IBD remain unclear, and effective treatment strategies have yet to be established. Herein, we developed oral gastroprotective βG@Apr‐WPG NMs (β‐glucan armored apremilast encapsulating tryptophan‐poly(lactic‐co‐glycolic acid)‐glutathione nanomicelles). This system effectively treats IBD and associated anxiety/depression by modulating the microbiota–gut–brain axis. βG@Apr‐WPG NMs demonstrated gastroprotection enhances retention, and enables sustained release within the inflamed colon, enhances drug solubility, and inflammation‐responsive apremilast release significantly improving oral therapeutic efficacy. Oral βG@Apr‐WPG NMs administration outperformed free apremilast by restoring gut barrier integrity, reducing histopathological damage, and modulating microbial dysbiosis. Systemic inflammation and neuroinflammation were markedly suppressed. Notably, the βG@Apr‐WPG NMs ameliorated anxiety‐ and depression‐like symptoms, as well as cognitive deficits in colitis‐induced mice, highlighting its therapeutic impact beyond the gut. Addressing reduced efficacy of conventional therapies, this multifunctional βG@Apr‐WPG NMs platform offers safe, simple, and highly efficient therapeutic strategy integrating targets intestinal inflammation, microbiota–gut–brain axis modulation, in the pathogenesis of IBD with comorbid neuropsychiatric disorders with confirmed safety.