Ulcerative colitis (UC) represents a chronic, relapsing inflammatory condition primarily affecting the colonic and rectal mucosa, presenting substantial challenges to healthcare systems globally. Conventional therapeutic approaches, including aminosalicylates, corticosteroids, immunosuppressants, and biological agents, face significant limitations including premature drug release, systemic toxicities, narrow therapeutic windows, and inadequate colonic accumulation. Hydrogel-based drug delivery systems have emerged as promising platforms for addressing these multifaceted challenges through their unique physicochemical properties, biocompatibility, and versatile functionalization capabilities. This comprehensive review examines the current landscape and future potential of hydrogel-enabled drug delivery for ulcerative colitis therapy, encompassing material design strategies, stimuli-responsive mechanisms, targeting approaches, and therapeutic cargo delivery. Natural polymer-based hydrogels, including polysaccharides and proteins, offer exceptional biocompatibility and intrinsic therapeutic properties, while synthetic and hybrid systems enable precise control over release kinetics and mechanical properties. Stimuli-responsive mechanisms, including pH, enzyme, and redox sensitivity, facilitate site-specific drug release in response to pathophysiological conditions unique to the inflamed colon. Advanced targeting strategies encompass mucoadhesive systems, cell-specific delivery, and inflammation-site accumulation mechanisms. The therapeutic cargo has expanded from traditional small molecules to encompass biologics, living therapeutics, and engineered nanomedicines. Novel formulation technologies, including injectable systems, microencapsulation approaches, and hybrid delivery platforms, demonstrate superior therapeutic efficacy in preclinical models compared to conventional formulations. Clinical translation faces challenges related to scalability, regulatory considerations, and personalized medicine implementation. Future perspectives point toward smart hydrogels with artificial intelligence integration, combination therapies, gut-brain axis targeting, and biomarker-guided precision medicine approaches. The convergence of materials science, biotechnology, and digital health technologies positions hydrogel-based therapeutics at the forefront of inflammatory bowel disease management, promising to transform treatment paradigms and improve outcomes for millions of patients worldwide.
