Hydrogel-encapsulated medium chain lipid-modified zeolite imidazole framework-90 as a promising platform for oral delivery of proteins

The administration of protein therapeutics through oral means is seen as a convenient and painless experience for patients, making it a significant consideration in the field of drug delivery. Nevertheless, the challenging conditions within the gastrointestinal tract, along with the obstacles to absorption, impede the efficient transportation of proteins. Here, we successfully implemented post-synthetic modifications to attach medium-chain lipids (C10) onto the surface of zeolitic imidazole framework-90 (ZIF-90), then encapsulated the nanoparticles with sodium alginate, resulting in a potential platform for the oral administration of proteins. By means of biomimetic mineralization, ZIF-90 achieves a simple and efficient encapsulation of proteins of varying sizes, while shielding them against degradation by digestive enzymes. Sodium alginate hydrogel protects proteins against gastric acid and helps the cargo to rapidly penetrate the mucus layer. Through a mixed mechanism dominated by micropinocytosis, the C10-conjugated ZIF-90 (ZIF-90-C10) can be uptake by Caco-2 cells with a 200–400% increase and transported through the Golgi apparatus after escaping from lysosomes, exhibiting enhanced uptake in the overall gastrointestinal tract. Furthermore, ZIF-90-C10 retains its adenosine triphosphate-responsive release, which drastically lowers the likelihood of accumulation in vivo and allows targeted delivery for disease cells. Our work highlights mid-chain lipid conjugation as a potent approach to enhancing nanoparticle delivery efficiency and a potential strategy for oral delivery of biomacromolecules when combined with pH-responsive gels.