Geometry‐Mediated Microgel Structure‐Mechanics for Intestinal Region‐Specific Probiotic Delivery

The physiological efficacy of functional food ingredients, particularly probiotics is highly dependent on their spatial localization within the intestine. The non-specific delivery of probiotics severely restricts their therapeutic efficacy. Herein, we developed a sustainable, food-grade microgel delivery platform assembled from corncob nanocellulose building blocks with distinct geometries for programmable intestinal probiotic release. Owing to their distinct topological structures and mechanical properties, spherical nanocellulose-based microgels (CNSM) were found to disintegrate in the ileum, while rod-like nanocellulose-based microgels (CNRM) retained intact until reaching the colon, where they subsequently ruptured. Molecular dynamics simulations supported the superior structural stability of CNRM against osmotic swelling, revealing a structure-mechanics driven mechanism for the controlled release pattern. Both microgels significantly enhanced probiotic survival, as well as nanocoating-mediated mucoadhesion and colonization. To maximize functionality, bile salt hydrolase-producing L. plantarum WCFS1 and immunomodulatory L. rhamnosus GG were embedded into CNSM and CNRM, respectively. Consequently, ileum-targeted WCFS1@CNSM significantly ameliorated hypercholesterolemia, accompanied by increased fecal cholesterol excretion and potential modulation of the gut-liver signaling axis whereas colon-targeted LGG@CNRM profoundly alleviated DSS-induced colitis through epithelial barrier restoration and inflammation suppression. This work provides a region-specific delivery strategy for next-generation probiotic therapeutics.