The development of effective oral drug delivery systems for targeted gut-to-liver transport remains a significant challenge due to the multiple biological barriers including the harsh gastrointestinal tract (GIT) environment and the complex protein corona (PC) formation. In this study, we developed ligand-modified nanoparticles (NPs) that enable gut-to-liver drug delivery by crossing the GIT and attenuating PC formation. Specifically, mesoporous silica nanoparticles (MSNs) were functionalized with peptides targeting the neonatal Fc receptor (FcRn), capitalizing on FcRn expression in the small intestine and liver for targeted drug delivery. We showed that MSNs decorated with a small cyclic FcRn binding peptide (MSNs-FcBP) obtained enhanced diffusion in intestinal mucus and superior transportation across the intestine compared to unmodified MSNs and MSNs decorated with a large IgG Fc fragment (MSNs-Fc), which correlated with diminished protein adsorption and weaker interaction with mucin. After entering the blood circulation, reduced serum PC formation by MSNs-FcBP reduces the proteolytic and phagocytic propensity of the reticuloendothelial system, ultimately ameliorating accumulation in hepatocytes. Pharmacokinetic and pharmacodynamic studies in diabetic mice revealed that MSNs-FcBP effectively transported the therapeutic agent exenatide across the intestinal epithelium, leading to a significant hypoglycemic response and improved glucose tolerance. This study underscores the critical role of ligand selection in limiting protein corona formation, thereby significantly enhancing gut-to-liver drug delivery by increasing mucus permeation and minimizing serum-protein interactions. The effective delivery of exenatide in diabetic mice illustrates the potential of this strategy to optimize oral drug bioavailability and therapeutic efficacy.
