Heteropolymer ferritin nanocages as delivery vehicles for oral delivery of GLP-1 peptides

Bioactive peptides have attracted significant attention for their potential health benefits; however, their oral administration is challenged by degradation from digestive proteases and limited intestinal absorption. In this study, we demonstrated the exceptional gastrointestinal stability of ferritin nanocages, which remained largely intact after 30 min of simulated gastric digestion and were highly resistant to intestinal proteolysis. Consistent with in vitro findings, orally administered ferritin successfully reached the intestinal tract without significant degradation in mice. We engineered a fusion protein by linking a glucagon-like peptide-1 (GLP-1) motif to the C-terminus of heteropolymer ferritin, generating HLG. Through Caco-2 monolayer assays, we confirmed that HLG absorption occurs primarily via TfR1-mediated endocytosis, followed by lysosomal trafficking and subsequent release of bioactive GLP-1. Oral administration of HLG significantly reduced blood glucose levels and food intake in type 2 diabetic mice, whereas the GLP-1 analog exenatide alone showed no such effects. These findings highlight the potential of ferritin-based nanocages as an effective oral delivery platform for bioactive peptides.