Oridonin‐Loaded <scp>PDA</scp> @Gel@ <scp>GO</scp> Nanocapsules Modulate <scp>NLRP3</scp> and Epithelial Repair in Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by sustained mucosal inflammation and epithelial barrier dysfunction, closely associated with aberrant NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. Targeted oral therapies that simultaneously suppress inflammation and promote mucosal repair remain limited. We developed an orally administrable nanomicrocapsule system (PDA@Gel@GO) for colon-targeted delivery of oridonin, a natural diterpenoid with anti-inflammatory activity. The system was constructed by encapsulating galactosylated carboxymethyl chitosan-based oridonin nanomicelles (GO) within gelatin microspheres, followed by polydopamine coating to enhance gastrointestinal stability and mucosal adhesion. In a dextran sulfate sodium (DSS)-induced UC mouse model, PDA@Gel@GO exhibited preferential accumulation in inflamed colonic tissues and significantly improved body weight loss, disease activity index, and colon shortening. Mechanistic studies demonstrated that PDA@Gel@GO treatment suppressed NLRP3 inflammasome activation, as evidenced by reduced expression of NLRP3, ASC, caspase-1, and IL-1β, accompanied by attenuation of oxidative stress and restoration of intestinal barrier proteins. Transcriptomic analysis further revealed activation of gene programs associated with epithelial regeneration, cell cycle progression, and DNA repair, suggesting coordinated inflammation resolution and mucosal repair. Collectively, this study presents a macrophage-targeted, multilayered nanomicrocapsule platform that enhances the therapeutic efficacy of oridonin through precise colon targeting and integrated anti-inflammatory and tissue-protective effects, providing a promising strategy for precision treatment of UC.