CROHNtrol – Local Combination Nanotherapy for Crohn’s Disease

Background and aims Crohn’s Disease (CD) is a chronic, relapsing form of Inflammatory Bowel Disease characterized by discontinuous, transmural inflammation that can affect any part of the gastrointestinal tract (GIT). Standard therapies typically rely on corticosteroids to induce remission, but their long-term use is limited by toxicity and side effects, making sustained disease control challenging. CHRONtrol proposes an orally administered dual-action therapy that integrates budesonide and teduglutide into smart delivery systems, allowing their local action. While budesonide controls inflammation, teduglutide promotes epithelial regeneration—a combination never before explored in CD treatment. By co-delivering these drugs in reactive oxygen species (ROS)-responsive nanoparticles (NPs), we aim to ensure site-specific release precisely where oxidative stress is elevated, thus maximizing local efficacy and minimizing systemic exposure. The nanocarriers are engineered with a polyethylene glycol (PEG) shell, enabling mucus penetration, but subsequent removal of PEG is imperative for cellular interaction. Leveraging the oxidative environment at the diseased colon epithelium, a ROS-sensitive thioketal (TK) linker is incorporated into the NPs, between the NPs matrix and the PEG, triggering the de-PEGylation of the system, and exposing the NP surface for effective epithelial retention. This design responds directly to key pathophysiological barriers in CD, including a disrupted epithelial barrier and thickened mucus. Methods The safety and efficacy of the combination therapy will be tested in vitro using a 3D intestinal inflammation model developed in our group. Different drug ratios will be explored to identify the most therapeutically effective combination. After achieving the most synergistic combination, its performance will be tested in SAMP1/YitFc mouse models. Anticipated impact CHRONtrol will deliver proof-of-concept data for a first-in-class dual-action nanotherapy, supporting its future translation into a scalable, oral treatment with improved efficacy and safety for patients with CD.