<p>Peptide drugs have gained considerable attention as new molecular entities, due to their high target specificity. However, oral delivery of peptides remains a major challenge, and current formulation approaches typically achieve only low single-digit bioavailability, prompting exploration of synergistic strategies to improve absorption. In this work, a self-unfolding foil device, designed for unidirectional drug release in close proximity to the intestinal mucosa, is combined with a potent permeation enhancer-based ionogel formulation for exploitation of synergies from two different oral delivery approaches. The choline decanoate ionogel is loaded into the foil, and insulin release optimized through hydrophilic surface modification and tailored cavity design. In vivo evaluation in rats demonstrate a bioavailability of 12.5% and a biopotency of 20% relative to subcutaneous administration representing approximately three- and four-fold increases, respectively, compared with the formulation control group. These findings demonstrate that unidirectional release from an advanced drug delivery system can markedly enhance formulation performance and pave the way for further development of similar combinatorial delivery strategies. Overall, this study reports the highest insulin bioavailability achieved with the self-unfolding foil platform to date, and among the highest reported in literature, highlighting its promise for advancing oral peptide delivery in future preclinical studies.</p> Graphical abstract <p></p>