Transformative therapy in acute microbial-induced colitis with inflammation triggered micelles and combination therapies.

Abstract

Ulcerative colitis has no cure and there are limited options for patients. Many current therapeutic drugs have poor bioavailability and targeting ability, including inhibitors of the cGAS-STING pathway, which has limited their clinical approval for colitis. Here we address this critical need through inflammation-triggered nanomicelles (ITMs) that are composed of biopolymer hyaluronic acid which specifically targets the inflamed colon by binding to CD44 receptors. ITMs encapsulate the cGAS inhibitor RU.521 improving the drug's overall bioavailability, and utilize a reactive oxygen species (ROS)-responsive thioketal linker, enabling site-specific drug release at the inflamed colon. The efficacy of ITMs was shown in a clinically relevant microbial-induced colitis model that recapitulates human colitis. Acute colitis was developed in gnotobiotic altered Schaedler's flora (ASF) IL-10 knockout mice infected with Helicobacter bilis or Escherichia coli 1D to induce severe and moderate colitis, respectively. Oral delivery of ITMs alone significantly reduced inflammation in the E. coli 1D model, while combining ITMs with anti-IL-12p40 antibodies mitigated disease severity in the H. bilis model as revealed by body weight recovery, reduced colon shortening, restoration of the intestinal epithelium, and reduction in proinflammatory cytokines. In vivo end points were validated with ex vivo tissue imaging and assays that identified the downregulation of cGAS expression and other mechanisms by which ITMs enable mucosal healing. These findings highlight the potential of ITMs for targeted, site-specific drug delivery as a novel IBD treatment strategy, and the importance of inhibiting the cGAS-STING pathway in inflammatory diseases.