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Here, we introduce a colon\u2010targeted, pH\u2010responsive hydrogel microalgal system (CV@PA\u2010gel) designed for synergistic treatment of IBD and its psychiatric comorbidities. This engineered platform co\u2010encapsulates the natural neuroprotective agent paeoniflorin (PA) and the gut\u2010microbiota modulator Chlorella vulgaris (CV) within a genipin\u2010crosslinked carboxymethyl chitosan\/sodium alginate matrix. The CV@PA\u2010gel 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\u2010gel outperforms free PA by more effectively restoring gut barrier integrity, ameliorating systemic and hippocampal inflammation, and rescuing anxiety\u2010, depressive\u2010like, and cognitive behaviors. Mechanistically, our findings suggest that gut\u2010derived systemic inflammation is associated with complement C3 activation and subsequent microglia\u2010mediated 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\u2010inducing factors. Our work establishes a versatile biomaterials strategy for disrupting the gut\u2010brain axis pathology, offering a powerful platform for the simultaneous management of intestinal and neuropsychiatric disorders.<\/jats:p>","DOI":"10.1002\/advs.202523551","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:42:31Z","timestamp":1776195751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Synergistic Hydrogel\u2010Microalgae Platform for Dual\u2010Targeting of Intestinal and Neuroimmune Dysfunction in Inflammatory Bowel Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Jing","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Psychiatry, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Zhejiang Key Laboratory of Precision Psychiatry  Hangzhou 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