Huiling Yan, Yixuan Li, Yixuan Li, Shanan Chen, Pengcheng Du, Kaiwen Wu, Hui Zhang, Kasper Hettinga, Lina Zhang, Gergely Toldi, Fazheng Ren, Yuan Li, Yuan Li
coordination or STMP-conjugated cross-linking of eco-friendly and biocompatible Artemisia sphaerocephala Krasch. polysaccharides (ASKP) extracted from desert sand-fixing plant; these microgels release lactoferrin (Lf) precisely in the small intestine or colon on-demand. Both microgels protect Lf from gastric digestion, preserve the Lf receptor (LfR)-binding domain, and facilitate efficient LfR-mediated endocytosis of Lf by intestinal epithelial cells. Small intestine-targeted microgels regulate Lf metabolism, boost Lf bioavailability by ≈6-fold, and drive marked hepatic Lf accumulation. These effects ameliorate alcoholic liver injury via the Nrf2-mediated antioxidant pathway and CPT1A-amplified fatty acid β-oxidation after oral uptake. Colon-targeted microgels alleviate ulcerative colitis by suppressing the TLR4/MyD88/NF-κB inflammatory axis and restoring gut microbiota homeostasis. Notably, this is the first demonstration of site-specific intestinal delivery achieved by using different cross-linking chemistries on the same ASKP backbone, enabling distinct gut-regional specific therapeutic actions. This work establishes food-grade microgel platforms as promising intestinal site-specific delivery systems for spatiotemporally controlled, on-demand delivery of bioactive proteins.