Oral biomacromolecule delivery is considered a promising alternative for patients who must receive long-term invasive injections, providing better patient compliance. However, it still faces great challenges due to the harsh gastrointestinal environment, including instability and poor intestinal absorption. Here, we report an antioxidant moiety (manganese ion, Mn4+)-assembled metal-organic framework (MOF) presenting functionalized coatings consisting of an inner layer of hyaluronic acid-polyethylene glycol and an outer layer of Eudragit® S100 for enhanced colon-targeted delivery of an anti-mouse tumor necrosis factor-alpha (TNF-α) antibody via oral route. The developed anti-TNF-α antibody-MOF system presented gastric resistance, enhanced targeting of the inflamed intestine, and antioxidant activity. In acute inflammatory bowel disease (IBD) models, the therapeutic effect of the oral anti-TNF-α antibody-MOF system was similar, or even better, than that of intravenous injections at the same antibody dose, with superior antioxidant and mucosal healing capacities. We also demonstrated that in a chronic murine colitis model, the oral anti-TNF-α antibody-MOF system significantly reduced the pathological features of the disease, especially the levels of proinflammatory factors and oxidation markers, which did not differ significantly from those in healthy mice. Overall, this study provides a promising strategy for the oral delivery of antibodies in IBD treatment.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.