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

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.