Engineering of Azo-Crosslinked Alginate Hydrogels for Targeted Oral Local Biologic Delivery

Abstract Oral delivery of therapeutic biologics is constrained by gastrointestinal degradation and premature leakage from physical hydrogels. Here, microfluidic-engineered azo-crosslinked alginate (SA-Azo) microspheres were fabricated via template-assisted covalent substitution, yielding uniform matrices with a diameter of 116.8 μm and a surface potential of −60 mV. The network achieved 52.8% encapsulation efficiency for infliximab, restricted leakage to under 1% over 48 h in simulated upper gastrointestinal fluids, and retained 90% bioactivity. In the colon, bacterial azoreductases selectively cleave the azo crosslinks, triggering matrix disassembly and payload release. Concurrently, the polyanionic backbone anchors electrostatically to positively charged inflamed mucosa, extending local retention. In murine colitis, oral infliximab-loaded microspheres restored colon length to 8.04 cm, lowered the disease activity index to 6.4, and downregulated serum IL-1β, IL-6, and TNF-α levels. This system offers a dependable strategy for targeted oral delivery of macromolecular therapeutics.