Synergistic Regulation of Ferroptosis via an Oral Solid Lipid Nanocomplex-Embedded Inulin Gel for Targeted Ulcerative Colitis Therapy.

Ulcerative colitis (UC), a chronic inflammatory disorder of the colon, remains challenging to treat due to limited efficacy with current therapies. Ferroptosis, a newly identified form of programmed cell death, contributes significantly to UC pathogenesis and might offer promising therapeutic potential. Herein, we developed an oral synergistic regulation of ferroptosis using a solid lipid nanocomplex-embedded inulin gel (SLN/Que&OA@Gel) for colon-targeted UC therapy; solid lipid was utilized to encapsulate oleic acid (OA) and quercetin (Que) for better intestinal bioavailability, which was further embedded in an inulin gel to realize colon targeting. The system combines OA─which modulates lipid composition to reduce ferroptosis susceptibility─with Que, an antioxidant that scavenges reactive oxygen species (ROS) and suppresses oxidative stress to limit ferroptosis progression. Simultaneously, the incorporation of the inulin gel matrix ensures gastrointestinal tract protection, mucoadhesion, prolonged retention time at the lesion site, and sustained drug release, which promise a better curative effect. In vivo studies demonstrate that SLN/Que&OA@Gel effectively remodels the UC-associated pathological microenvironment by alleviating intestinal damage, restoring intestinal barrier integrity, and reducing inflammation. This strategy of synergistic regulation of ferroptosis and microenvironment remodeling presents a promising therapeutic avenue for UC management.