Abstract

Inflammatory bowel disease (IBD) management remains a significant challenge due to its complex pathogenesis. While current therapies for IBD are effective in symptom management, a radical cure remains elusive. However, the high cost, adverse effects, and acquired drug resistance limit their long-term use, further highlighting the pressing need for safer, multifunctional, and precise therapeutic strategies. Herein, we developed a novel iron-based nanozyme (DHM-Fe) by coordinating dihydromyricetin (DHM) with iron ions. The DHM-Fe nanozyme confers antioxidant and anti-inflammatory effects by mimicking SOD/CAT activities and suppressing M1-like macrophage polarization. To improve gastric stability and targeting, the DHM-Fe nanozyme was encapsulated in yeast microcapsules (YM), forming the DF@YM oral delivery system. Oral administration of DF@YM exhibited good biocompatibility and alleviated DSS-induced colitis by suppressing pro-inflammatory responses, restoring barrier integrity, and modulating gut microbiota composition towards homeostasis. Metabolomic and molecular docking analyses revealed that DF@YM alleviates intestinal inflammation, potentially through activating the aryl hydrocarbon receptor (AhR)/IL22 pathway. Furthermore, direct visualization via mass spectrometry imaging confirmed that DF@YM markedly enhances the tissue-specific accumulation of DHM. As an oral delivery system for natural compounds, this multifunctional strategy enables precise targeting and synergistic regulation of the intestinal microenvironment, presenting a promising avenue for IBD treatment.