Oral Lipid-Based Nanomedicine for the Inhibition of the cGAS-STING Pathway in Inflammatory Bowel Disease Treatment.

Harnessing the effect of the cyclic GMP-AMP Synthase-STimulator of INterferon Genes (cGAS-STING) signaling pathway has emerged as a promising approach to developing novel strategies for the oral treatment of inflammatory bowel disease (IBD). In this work, we screened different cGAS-STING inhibitors in murine macrophages. Then, we encapsulated the cGAS-STING inhibitor H-151 within lipid nanocapsules (LNCs), owing to their inherent ability to induce the secretion of glucagon-like peptide 2 (GLP-2), a re-epithelizing peptide, upon oral administration. We demonstrated that our formulation (LNC(H-151)) could induce GLP-2 secretion and selectively target the cGAS-STING pathway and its downstream key markers (including TBK1 and pTBK1) while reducing the expression of pro-inflammatory cytokines associated with the cGAS-STING pathway (TNF-α and CXCL10) in murine macrophages. In an acute dextran sodium sulfate (DSS)-induced colitis mouse model, the oral administration of LNC(H-151) significantly reduced pro-inflammatory cytokines to levels comparable to the CTRL Healthy group while promoting mucosal healing. The therapeutic potential of this scalable and cost-effective nanomedicine warrants further investigation as an alternative for the oral treatment of IBD.