A dual-crosslinked herbal hydrogel for multimodal therapy of ulcerative colitis via IL-34/IL-22 modulation

Abstract

Ulcerative colitis (UC) represents a prevalent idiopathic inflammatory disease characterized by impaired mucosal repair, gut microbiotal dysbiosis and compromised immune function. Conventional therapeutic approaches predominantly focus on symptom management, frequently resulting in the excessive use of pharmaceuticals. Herein, we report a dual-crosslinked gel system (GE-GA@GP gel, abbreviated as GG gel) composed of Gardenia jasminoides E llis polysaccharide (GP) and glycyrrhizic acid (GA) loaded with geniposide (GE) to simultaneously target barrier dysfunction and immune dysregulation. Derived from natural sources, these functional ingredients form hydrogel structures through spontaneous molecular self-assembly, ensuring excellent biocompatibility. Specifically, the GP imparts pH-responsive properties to the GG gel, thus enhancing therapeutic efficacy. Additionally, GA increases epithelial membrane fluidity, promoting the transmembrane transport of GE and enhancing drug penetration into the inflamed tissues. In vivo evaluations demonstrate that the GG gel exerts its therapeutic effect by restoring damaged mucosal tissues, modulating intestinal mucosal immune responses, and rebalancing gut microbial homeostasis. Mechanistic investigations demonstrate that the GG gel enables effective intervention against UC by activating IL-22 expression to mediate intestinal mucosal repair, suppressing IL-34 expression to attenuate intestinal inflammatory infiltration, and promoting macrophage polarization to exert synergistic therapeutic effects. Collectively, this study presents a comprehensive multimodal therapeutic approach that integrates the restoration of the physical barrier, regulation of gut microbiota, and robust modulation of deep-seated immune dysregulation, thereby offering an effective strategy for the treatment of UC.