Intestinal Source Control of Lipid Metabolism by Enzyme-Probiotic Encapsulated, Spatiotemporal Crosslinked, and Small Intestine-Adhesive Hydrogel Microspheres.

Probiotic therapy that targets fat absorption in the small intestine holds considerable potential for regulating lipid metabolism, yet it faces challenges related to spatiotemporal delivery and colonization efficiency. To address these issues, an enzyme-probiotic biohybrid (AKK-COD) has been developed and subsequently encapsulated in thiol-modified alginate hydrogel microspheres. This therapeutic system enables sequential functions: intragastric protection, small intestinal adhesion, and probiotic release and colonization. The Ca2+-crosslinked 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-COD, 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-fat diet-induced hypercholesterolemia, offering a safe and efficient strategy for lipid-lowering therapies.