Iron-mimic peptide converts transferrin from foe to friend for orally targeting insulin delivery

Oral administration of targeted nanoparticles (NPs) has great potential in biomedical applications and displays several putative advantages for protein and peptide drug delivery. However, one important limiting factor is the presence of free ligands or endogenous counterparts, which competitively inhibit the ligand-receptor interaction of the actively targeted NPs. We hypothesize that NPs targeted to the transferrin (Tf) and transferrin receptor (TfR) complex may overcome this competitive inhibition. To test this hypothesis, herein, we develop CRT-peptide-modified NPs, which target the Tf-TfR complex, and compare their performance with HAI-peptide-modified NPs which only target TfR. The results of our study show that in the presence of free Tf, the CRT NPs exhibit higher cellular internalization, better Caco-2 monolayer transportation, and increased villi absorption compared with the HAI NPs. Meanwhile, the epithelium transportation of the CRT NPs is lower compared with the HAI NPs in the absence of free Tf, which demonstrates the assistance of Tf. The better intestinal absorption of the CRT NPs is induced by the unique properties of the CRT ligand, which could target the Tf-TfR complex with a non-canonical allosteric directed mechanism. The in vivo study demonstrates a 1.9-fold higher bioavailability for the CRT NPs compared with the HAI NPs. Our results verify that this targeting strategy not only avoids the competitive inhibition of endogenous Tf, but also converts endogenous Tf from foe to friend for active targeting.