Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles

• Published in: ACS nano Vol. 18; no. 19; pp. 12117 - 12133
• Main Authors: Uthaman, Saji, Parvinroo, Shadi, Mathew, Ansuja Pulickal, Jia, Xinglin, Hernandez, Belen, Proctor, Alexandra, Sajeevan, Karuna Anna, Nenninger, Ariel, Long, Mary-Jane, Park, In-Kyu, Chowdhury, Ratul, Phillips, Gregory J., Wannemuehler, Michael J., Bardhan, Rizia
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.05.2024
• Subjects: Animals; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Humans; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Micelles; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - metabolism; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; Inflammatory bowel disease; ROS-responsive nanoparticles; small-molecule inhibitor; micelles; cGAS-STING pathway; hyaluronic acid
• ISSN: 1936-0851; 1936-086X; 1936-086X
• DOI: 10.1021/acsnano.3c11257

Ulcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitro studies in macrophages and in vivo studies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis’s severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivo end points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.