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To address these issues, an enzyme\u2010probiotic biohybrid (AKK\u2010COD) has been developed and subsequently encapsulated in thiol\u2010modified alginate hydrogel microspheres. This therapeutic system enables sequential functions: intragastric protection, small intestinal adhesion, and probiotic release and colonization. The Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010crosslinked hydrogel maintains structural integrity under acidic gastric conditions, ensuring protection of probiotics and enzymes while facilitating timely gastric emptying. Upon reaching the small intestine, the microspheres adhere to the small intestinal mucosa via disulfide linkage, enhancing local retention. Concurrently, the gradual dissociation of ionic crosslinks within the hydrogel allows the release of AKK\u2010COD, which participates in the catalytic conversion of cholesterol, modulates lipid absorption pathways, and promotes microbial homeostasis. In vivo experiments demonstrate that this approach significantly alleviates high\u2010fat diet\u2010induced hypercholesterolemia, offering a safe and efficient strategy for lipid\u2010lowering therapies.\n                  <\/jats:p>","DOI":"10.1002\/advs.75362","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T12:37:03Z","timestamp":1778243823000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intestinal Source Control of Lipid Metabolism by Enzyme\u2010Probiotic Encapsulated, Spatiotemporal Crosslinked, and Small Intestine\u2010Adhesive Hydrogel Microspheres"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaolin","family":"Wu","sequence":"first","affiliation":[{"name":"Department of General Surgery The Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai P. R. 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