Transforming a protease inhibitor into a peptide Guardian: BBI-armed hydrogel beads for Oral delivery of active peptides.

This study repurposes the Bowman-Birk inhibitor (BBI), traditionally viewed as an antinutritional factor for its protease inhibition, as a protective agent for peptide therapeutics. We co-encapsulated BBI with semaglutide in hydrogel beads to orchestrate their release, thereby leveraging protease inhibition to enhance peptide stability. In vitro studies with ionically crosslinked beads showed that BBI release effectively inhibited trypsin. Crucially, this extended semaglutide's intestinal residence time from 2.5 to 4 h (1.6-fold increase over control, p < 0.05), showcasing a direct protective benefit. Release kinetics revealed a temporal synergy: early-phase BBI release (60% within 2 h) established a low-protease environment enabling sustained semaglutide release. Our findings not only offer a novel strategy for oral peptide delivery but also redefine antinutritional factors as valuable functional excipients in drug formulation.