Advancing Inflammatory Bowel Disease Treatment by Targeting the Innate Immune System and Precision Drug Delivery

Abstract

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Current immune-modulating therapies are insufficient for 30-50% of patients or cause significant side effects, emphasizing the need for new treatments. Targeting the innate immune system and enhancing drug delivery to inflamed gut regions are promising strategies. Neutrophils play a central role in IBD by releasing reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) -DNA-based structures with cytotoxic proteins-that contribute to mucosal damage and inflammation. Recent studies linking ROS production, DNA repair, and NET formation have identified NETs as potential therapeutic targets, with preclinical models showing positive outcomes from NET inhibition. Innovative oral drug delivery systems designed to target gut inflammation directly-without systemic absorption-could improve treatment precision and reduce side effects. Advanced formulations utilize properties such as particle size, surface modifications, and ROS-triggered release to selectively target the distal ileum and colon. A dual strategy that combines a deeper understanding of IBD pathophysiology to identify inflammation-related therapeutic targets with advanced drug delivery systems may offer significant promise. For instance, pairing NET inhibition with ROS-responsive nanocarriers could enhance treatment efficacy, though further research is needed. This synergistic approach has the potential to greatly improve outcomes for IBD patients.

Keywords: colonic drug delivery; drug targets; inflammatory diseases; optimize treatment; pharmacology.

Figure 1

(A) Interactions between luminal content, such as gut-residing microbes, and the intestinal surface can activate innate immune responses that subsequently cause inflammation in the gut. The mechanisms with therapeutic potential are evaluated in this review. (B) Drug delivery strategies for targeting inflamed gut. Abbreviations: PAD, protein arginine deiminase; ROS, reactive oxygen species; NETs, neutrophil extracellular traps; ECM, extracellular matrix. Created in BioRender. Kiilerich, K.F. (2024) https://BioRender.com/h24q574 (accessed on 8 August 2024).

Figure 2

Physiological factors relevant for drug delivery to IBD patients. Physiological and microbial changes in IBD patients impact gastrointestinal motility, water resorption, pH, and microbiome diversity. Water content. In healthy individuals, water content decreases along the gastrointestinal tract, but in IBD patients, reduced water absorption in the colon leads to increased stool water content. Microbial diversity. Healthy individuals exhibit increasing microbial diversity through the gastrointestinal tract, whereas IBD patients show reduced diversity, known as dysbiosis. Transit time. In healthy individuals, drug passage time increases along the gastrointestinal tract. In IBD patients, the small intestine’s transit time is prolonged, while colonic transit is accelerated, complicating time- or site-specific drug delivery. pH. Healthy subjects experience a gradual pH decrease along the gastrointestinal tract. In IBD patients, pH is higher in the duodenum and lower in the colon compared to healthy individuals. Mucosal inflammation further disrupts motility, intestinal volume, and integrity, influencing both drug absorption and microbial metabolism. Created in BioRender. Kiilerich, K.F. (2024) BioRender.com/v02x038 (accessed on 16 August 2024), based on Hua et al., 2015 [54], with permission from Elsevier.