A Synergistic Hydrogel‐Microalgae Platform for Dual‐Targeting of Intestinal and Neuroimmune Dysfunction in Inflammatory Bowel Disease

ABSTRACT Inflammatory bowel disease (IBD) is frequently complicated by comorbid depression and anxiety, creating a therapeutic vicious cycle that is currently managed with fragmented, non‐integrated treatments. Here, we introduce a colon‐targeted, pH‐responsive hydrogel microalgal system (CV@PA‐gel) designed for synergistic treatment of IBD and its psychiatric comorbidities. This engineered platform co‐encapsulates the natural neuroprotective agent paeoniflorin (PA) and the gut‐microbiota modulator Chlorella vulgaris (CV) within a genipin‐crosslinked carboxymethyl chitosan/sodium alginate matrix. The CV@PA‐gel exhibits minimal drug release in the stomach but provides sustained, targeted release in the colon, significantly enhancing the oral bioavailability and intestinal retention of its cargo. In a murine model of chronic colitis, CV@PA‐gel outperforms free PA by more effectively restoring gut barrier integrity, ameliorating systemic and hippocampal inflammation, and rescuing anxiety‐, depressive‐like, and cognitive behaviors. Mechanistically, our findings suggest that gut‐derived systemic inflammation is associated with complement C3 activation and subsequent microglia‐mediated polarization of neurotoxic A1 astrocytes in the hippocampus, leading to synaptic loss. PA, delivered precisely by the hydrogel, directly suppresses this cascade by inhibiting microglial release of key A1‐inducing factors. Our work establishes a versatile biomaterials strategy for disrupting the gut‐brain axis pathology, offering a powerful platform for the simultaneous management of intestinal and neuropsychiatric disorders.