Azo-Linked 5-ASA Hydrogel Microparticles with Enzyme Shielding for Sustained Drug Release in Ulcerative Colitis Therapy

Inflammation-targeted delivery of anticolitic drugs remains a key challenge due to premature enzymatic activation and poor tissue specificity. Here, we report hydrogel microparticles from azo-linked 5-aminosalicylic acid covalently grafted onto partially oxidized sodium alginate (SA-AP). Ca2+-induced cross-linking formed spherical microparticles with tunable interfaces for physical and electrostatic protection. These exhibited high stability in simulated gastric and intestinal fluids, preventing premature 5-ASA release. Colonic bacterial reductase triggered sustained release after a 4 h lag, limited by hydrogel diffusion barriers. Adhesion assays showed selective binding to positively charged inflamed-mimetic surfaces, and cellular studies confirmed anti-inflammatory efficacy. In a DSS-induced murine colitis model, SA-AP microparticles outperformed free 5-ASA, reducing disease activity index scores, preserving colon length, attenuating systemic inflammation, and lowering proinflammatory cytokines. Histology revealed restored epithelial architecture and goblet cells with minimal infiltration. This system enables effective therapy at 30 mg kg–1 5-ASA, a 60% dose reduction versus similar cases.