Investigation of FcRn‐Mediated Transepithelial Mechanisms for Oral Nanoparticle Delivery Systems

Abstract Oral delivery is the most widely used modality for drug administration, but its efficiency is hampered by the limited drug absorption in the gastrointestinal tract. To address this issue, neonatal‐Fc‐receptor‐targeted liposome (Fc domain‐binding peptide (FcBP)‐Lip) is designed in this study. It is discovered that FcBP modification, by adapting to longitudinal pH gradience of the intestine, increases the unidirectional transport of liposomes from the apical to the basolateral side of the intestinal epithelium. In addition, FcBP‐Lip circumvents the lysosomal sequestration and engages the endoplamic reticulum (ER)–Golgi secretion pathway, together contributing to another mechanism that enhances epithelium transcytosis. Moreover, it is discovered that FcBP‐Lip is subject to paracellular and lymphatic transportations by activating specific intracellular kinases and forming chylomicron, respectively. Owing to the vigorous involvement of the miscellaneous transepithelial transport pathways, oral absorption of FcBP‐Lip in vivo is significantly increased. Finally, the insulin that is encapsulated into FcBP‐Lip elicits a stronger hypoglycemic effect than the native form. Notably, insulin‐loaded FcBP‐Lip efficiently elevates hepatic insulin accumulation, insulin receptor level, and glycogen production, leading to blood glucose homeostasis in diabetic rats.