Remodeling the intestinal microecology to break the vicious cycle of IBD with an oral pH-responsive zinc-gallic acid nanocomplex

Intestinal microecological disruption, characterized by a vicious cycle of epithelial barrier dysfunction and microbial dysbiosis, is a critical driver of inflammatory bowel diseases (IBD). A compromised epithelial barrier facilitates the invasion of pathogens, which further exacerbates the mucosal damage through immune response and inflammatory cascades. Herein, an oral, hierarchically pH-responsive metal-polyphenol nanocomplex (Zn-GA@ES100) with synergistic antimicrobial and barrier-restoring functions is developed to interrupt this cycle. The nanocomplex is founded on a “carrier-is-the-drug” principle, where a core nanoparticle composed of zinc ions (Zn 2+ ) and gallic acid (GA) is coated with an enteric Eudragit® S100 (ES100) shell. ES100 protects the nanocomplex from gastric acid, dissolving only in the intestine. Upon reaching the acidic microenvironment of inflamed sites, the Zn-GA core specifically disassembles to release Zn 2+ and GA. Zn 2+ selectively suppresses the expansion of pathogenic bacteria ( E. coli and S. aureus ) to regulate the gut microbiome, while GA enhances epithelial barrier integrity by increasing tight junction (TJ) proteins (claudin-5, occludin-1, and ZO-1) via the Nrf2/HO-1 pathway. Consequently, Zn-GA@ES100 demonstrates potent therapeutic efficacy in a DSS-induced colitis model, efficiently reprogramming the gut microecology by concurrently eliminating pathogens and repairing the epithelial barrier. This nanoplatform highlights a powerful and precise therapeutic strategy for IBD.