The Inflamed Intestinal Barrier as a Formulation Variable in Oral Nanocarrier Design: Evidence-Informed Principles for Mucus Interaction, Epithelial Access, and Translational Testing.

Oral nanocarrier development for inflammatory bowel disease (IBD) is complicated by inflammation-dependent changes in mucus, epithelial integrity, and immune-cell interactions. This critical narrative review examines comparative evidence from in vitro systems, animal models, and human intestinal tissue, alongside clinical studies, to assess how barrier state modifies formulation performance. Across the reviewed studies, particle size alone does not consistently predict lesion accumulation, while surface chemistry, coating, geometry, and stability in gastrointestinal fluids influence mucus interaction, cellular access, and payload release. Tissue-associated fluorescence, increased permeability, and cellular uptake do not independently establish intact-carrier transport or productive delivery. Clinical trials of selected oral nano-enabled formulations report improvements in some disease outcomes but do not establish inflammation-selective delivery as the underlying mechanism. We propose an evidence-informed benchmarking framework linking characterization in biological media to mucus transport or retention, epithelial-immune responses, spatial localization, target engagement, and safety. Matched healthy and inflamed comparators are central to testing selectivity, and preclinical findings must be distinguished from clinical validation. Artificial intelligence may support barrier-state-aware formulation optimization but requires standardized datasets and prospective experimental validation. Given the heterogeneous evidence base and limited direct human delivery studies, prospective validation should prioritize local payload delivery and therapeutic benefit without exacerbating intestinal barrier injury.