Abstract

Over the past decades, antibodies have become indispensable tools due to their high specificity and versatility. Egg yolk antibody (IgY), a natural protein biomaterial noted for its biosafety, thermal stability, and cost-effective, is particularly suitable for long-term interventions in chronic diseases. Its intrinsic biocompatibility allows safe oral administration, while its structural robustness facilitates diverse delivery formats such as bioactive formulations or coatings. This makes IgY a promising candidate for managing conditions like inflammatory bowel disease (IBD), including ulcerative colitis (UC), which require prolonged, well-tolerated therapeutic strategies. However, the antigen-specific therapeutic potential of IgY in IBD remains underexplored. Here, we propose to use an engineered anti-TNFR1 IgY as an oral therapeutic agent for UC intervention as a TNFR1-selective strategy. Anti-TNFR1 IgY exhibited superior gastrointestinal stability to mammalian IgG and suppressed the production of key inflammatory mediators, such as IL-6 and MMP9, in stimulated RAW264.7 macrophages. In a DSS-induced murine colitis model, oral administration of anti-TNFR1 IgY significantly alleviated inflammation, evidenced by reduced biomarkers (calprotectin, IL-6, TNF-α) and elevated IL-10, alongside improved behavioral manifestations and attenuated histopathological staining. Moreover, it retained bioactivity following heating, freeze-drying, and hydrogel encapsulation, supporting its potential as a scalable robust bioactive building block. Our work highlights antigen-specific IgY as a biocompatible biomaterial-based strategy for long-term immunomodulation in intestinal inflammation. This platform may help connect orally administered targeted therapy with gastrointestinal health management.