A Microgel Platform Enables Site‐Specific Intestinal Delivery of Lactoferrin, Improving its Bioavailability for Targeted Alleviating Liver Injury and Colitis

ABSTRACT Oral delivery of bioactive proteins remains a challenging area, as it demands effective gastric protection and intestinal site‐specific release. We design two intestinal site‐specific microgels via Fe ^{3 +} ‐COO ⁻ 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.