Enzyme-Responsive Polymeric Drug Delivery Systems for the Treatment of Inflammatory Bowel Diseases: A Review

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that imposes an increasing global health burden. Conventional pharmacological treatments are often limited by systemic side effects and insufficient drug accumulation at inflamed intestinal sites. Enzyme-responsive polymeric drug delivery systems have emerged as a promising strategy to overcome these limitations by enabling site-specific and controlled drug release within the pathological microenvironment of the colon. This review summarizes recent advances in enzyme-responsive polymeric platforms designed for IBD therapy. We first discuss the altered enzymatic landscape in the intestinal microenvironment of IBD, including host-derived inflammatory enzymes such as esterases, matrix metalloproteinases, and hyaluronidase, as well as microbiota-derived enzymes such as azoreductase, cellulase, and amylase. These enzymes provide intrinsic biological triggers for selective polymer degradation and drug release. We then categorize enzyme-responsive polymeric delivery systems according to the enzymes involved and highlight representative material design strategies, including polymer prodrugs, core-shell nanocarriers, enzyme-degradable hydrogels, and polysaccharide-based carriers. Particular emphasis is placed on the multifunctional roles of polymers that enable targeted delivery, mucosal adhesion, and therapeutic synergy through bioactive degradation products. Finally, current challenges and future directions toward multi-stimuli-responsive systems and clinically translatable polymeric nanomedicine for precision IBD therapy are discussed.