Efficient oral insulin delivery with sustained release by folate-conjugated metal-organic framework nanoparticles

Oral protein/peptide delivery systems have garnered global interest due to their potential to provide substantial benefits to patients. However, their clinical translation has been impeded by challenges pertinent to poor intestinal permeability, acid instability, and the short half-life of proteins/peptides. Here, we report a simple, efficient, and sustained-release oral insulin delivery system based on folic acid (FA)-conjugated acid-resistant metal-organic framework (MOF) nanoparticles with high drug-loading capacity. The FA conjugation on MOF (PCN-777) nanoparticles not only selectively augmented intestinal transportation efficiency in diabetic animals via upregulated intestinal FA transporter-mediated endocytosis but they also tuned PCN-777 disintegration in the phosphate-rich bloodstream environment to sustain long-acting basal insulin release kinetics within a narrow therapeutic range. In diabetic animal models, the FA-PCN-777 oral insulin delivery nanosystem exhibited a smooth hypoglycemic effect for up to 48 h and a markedly high bioavailability of 35.5%, representing a potential long-acting oral formulation with reduced hypoglycemia risk.