Mechanistic Insights into a Smart Nanomotor‐Laden Inulin Hydrogel Reprogramming Gut‐Brain Axis for Combinatorial Inflammatory Bowel Disease‐Depression Therapy

Abstract Depression prevalence is significantly higher (20‐40%) in inflammatory bowel disease (IBD) patients than the general population. Dysregulation of the gut microbiota‐brain axis (GM‐BA) is implicated in IBD‐associated depression pathogenesis, involving M1 macrophage‐driven neuroinflammation. While glycyrrhizic acid (GA) possesses anti‐inflammatory and neuroprotective properties, its poor oral absorption limits clinical use. To overcome this, we developed an innovative oral delivery system, IN@MOTOR@GA (IMG). It consists of Janus nanomotors encapsulated within an inulin hydrogel. The hydrogel protects the nanomotors in the stomach and enables targeted colonic release. At inflamed sites, the nanomotors utilize overexpressed H 2 O 2 to generate oxygen propelling autonomous motion, enhancing drug penetration and alleviating hypoxia. Metabolized inulin acts as a prebiotic, promoting probiotic growth and restoring gut microecology. In vivo studies demonstrated that IMG significantly alleviated murine colitis, restoring mucosal integrity and reducing pro‐inflammatory cytokines. Critically, IMG mitigated hippocampal neuroinflammation by modulating peripheral immunity and promoting a neuroprotective microglial phenotype, ultimately improving depressive‐like behaviors. This study introduces a groundbreaking GM‐BA‐targeted therapy offering a novel strategy for synergistic IBD and psychiatric comorbidity management.