Intestinal-inflammation-targeted delivery of microbial metabolite attenuates immune checkpoint inhibitors-mediated colitis 2842

Abstract Description Despite significant advances in cancer immunotherapies with immune check point inhibitors (ICI), ICI-mediated colitis (IMC) remains a significant challenge for cancer patients. Current drug therapies against IMC have limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we have developed novel inflammation-targeted nanoparticles (ITNPs) using polymers from Cochlospermum gossypium plant, combined with compritol ATO 888, transcutol P and vitamin E TGPS. These ITNPs were used to deliver the microbial metabolite urolithin A (UroA) and its potent synthetic analogue UAS03 to the inflamed regions of the intestines to mitigate IMC. Our data suggested that ITNPs can specifically bind to and accumulate within the inflamed regions of both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the affected tissues. Importantly, oral administration of ITNPs loaded with UroA or UAS03 significantly attenuated both chemical- and immune checkpoint inhibitor-induced colitis in preclinical models. Treatment with ITNP-UroA/UAS03 in these models reduced systemic inflammation, intestinal permeability, inflammatory cell-infiltration in to the colon, and restored intestinal tight junction proteins, repaired epithelial cell damage. In conclusion, the targeted delivery of UroA/UAS03 at gut-inflamed sites holds great promise for mitigating immune-related adverse events (e.g., colitis) during cancer immunotherapy. Funding Sources VRJ: NIH/NIGMS CoBRE grant (P20GM125504-01), NIH/NIDDK (R01DK135603-01A1), NIH/NIEHS (P30ES030283), NIH/NCI (CA191683), NIH/NIAAA (R21AA030638), The JHFERE Grant, Dept. of Microbiology and Immunology and UofL-BCC. Hyperion experiments were supported by NIH/NIGMS CoBRE Functional immmunomics core (P20GM135004) PKV: DBT, Institute for Stem Cell Science and Regenerative Medicine (DBT-inStem) Topic Categories Mucosal and Regional Immunology (MUC)