Oral multifunctional gel beads for the targeted treatment of inflammatory bowel disease

Current IBD therapies face limitations such as systemic toxicity, off-target effects, and microbiota dysbiosis. We developed an oral multifunctional gel bead integrating three innovations: (1) a butyrate–apigenin synergy that inhibits NF-κB via CK2/p65 phosphorylation suppression, activates a PPAR-γ-mediated metabolic shift to β-oxidation, and modulates the microbiota by enhancing Bacteroidetes/suppressing Enterobacteriaceae; (2) an apigenin–butyrate ester prodrug overcoming organoleptic issues while enabling CK2 targeting; and (3) a pH/enzyme–responsive delivery system using the FDA-approved ascorbyl palmitate/alginate, achieving gastric protection, charge–mediated colitis targeting, and esterase–triggered release. In colitis model mice, gel beads restore clinical parameters, intestinal integrity, and microbial balance, outperforming apigenin-butyrate ester and 5-ASA at half-doses with extended intervals. It significantly downregulated colon CK2 expression (4.07-fold) and the phospho-P65/total P65 ratio (3.04-fold). This integrated strategy combining multimodal drug actions and precision delivery establishes a new paradigm for efficient and alternative IBD therapeutics with reduced dosing requirements.