pH-Responsive Hydrogels for Oral Colon-Targeted Delivery of Biologics: Recent Advances

Colonic diseases — inflammatory bowel disease, colorectal malignancy, and infectious colitis — require targeted pharmacological intervention at the large intestinal mucosa. Biologic therapeutics such as monoclonal antibodies, recombinant proteins, nucleic acid-based therapies, and extracellular vesicles possess excellent target specificity but face near-complete oral bioavailability failure owing to the sequential degradation imposed by the gastrointestinal tract: acid-mediated unfolding, enzymatic proteolysis, mucus barrier entrapment, and epithelial tight junction restriction. pH-responsive hydrogels exploit the predictable rise in intraluminal pH from the stomach (pH 1.2–2.0) to the ileocolonic junction (pH 6.8–7.4) to achieve site-selective colonic biologic release. These ionisable, crosslinked polymer networks remain structurally compact and protective under acidic gastric conditions, then undergo thermodynamically driven swelling through Donnan osmotic pressure generation and electrostatic repulsion upon carboxylate group ionisation at colonic pH, enabling controlled macromolecular diffusion. This comprehensive review covers the mechanistic basis of pH-responsive swelling from thermodynamic and kinetic perspectives — including Flory-Rehner theory, Donnan osmotic swelling, mesh size dynamics, and Korsmeyer-Peppas drug release modelling — alongside polymer chemistry, formulation design, figure-based schematic analysis, and clinical translation. Ten summary tables and multiple schematic figure descriptions organise GI environmental parameters, polymer benchmarks, swelling thermodynamics, drug release kinetics, biologic delivery outcomes, fabrication approaches, crosslinking strategies, characterisation methods, clinical evidence, and translational challenge-solution pairings