Colon‐Targeted Natural Polysaccharide‐Berberine Armored Hydrogel for the Treatment of Colitis

Abstract The maintenance of gut immune homeostasis and microbial balance is pivotal in the pathogenesis and progression of ulcerative colitis (UC). Despite advances in therapy, effective UC management remains challenging due to the limited efficacy and significant side effects of conventional treatments. Inspired by the synergistic mechanisms of bioactive compounds in traditional Chinese medicine, a colon‐targeted hydrogel integrating rhubarb‐derived polysaccharides and berberine‐loaded dendrimers is engineered. This hydrogel self‐assembles via intermolecular hydrogen bonding and electrostatic interactions, enabling localized accumulation in colonic tissues to suppress aberrant immune activation and remodel the dysbiotic microbiome. Mechanistic studies reveal that the hydrogel potently promotes the polarization of anti‐inflammatory M2 macrophages while suppressing pro‐inflammatory cytokine secretion, resulting in significant amelioration of colitis symptoms in murine models. Importantly, the therapeutic intervention not only restored gut microbiota composition but also corrected metabolic disturbances, collectively contributing to the re‐establishment of intestinal homeostasis. The findings underscore the potential of this polysaccharide‐based hydrogel as an effective oral therapeutic strategy for UC while demonstrating the translational value of combining natural bioactive constituents for targeted drug delivery.