Synthetic mucus biomaterials enable localized therapeutic antibody delivery in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent gastrointestinal inflammation that requires long-term therapeutic intervention. While anti-TNF-α monoclonal antibodies (mAbs) are effective in maintaining remission in IBD, systemic delivery is associated with immunosuppression, poor targeting efficiency, and high cost. To address these limitations, we developed a synthetic mucin-based hydrogel for localized delivery of TNF-α-targeting mAbs. Mucins are heavily glycosylated biopolymers that naturally bind antimicrobial and anti-inflammatory proteins, making them well-suited for local biologic drug delivery at mucosal sites. Synthetic mucin-based hydrogels were formed by cross-linking mucin harvested from porcine small intestine with a 4-arm PEG-thiol and loaded with mAbs to evaluate biocompatibility, antibody release kinetics, and therapeutic efficacy. <i>In vitro</i> studies confirmed cytocompatibility of mucin-based hydrogels and demonstrated diffusion-dependent release of full-length IgG antibodies, with enhanced release under proteolytic conditions simulating the gastrointestinal environment. Moreover, mucin-based hydrogels alone were found to modulate macrophage activation in a stiffness dependent manner and dampen inflammation in lipopolysaccharide (LPS)-stimulated macrophages. Treatment of LPS-stimulated macrophages with mAb-loaded hydrogels reduced pro-inflammatory cytokine production and macrophage activation, confirming retention of mAb bioactivity. Compared to antibodies administered in solution, <i>in vivo</i> biodistribution studies revealed greater absorption of antibodies when loaded in mucin-based hydrogels and administered via enema in trinitrobenzene sulfonic acid-induced colitis mice, likely due to enhanced adhesion to mucosal epithelium and slowed intestinal clearance. This study demonstrates the potential of mucin-based hydrogels as a platform for local mAb delivery in IBD, enabling targeted immunosuppression while minimizing systemic exposure.