Transcytosis-Guided Intestinal Absorption of Ultrasmall Gold Nanoparticles for Lymphatic Entry into Systemic Circulation

Abstract The intestinal epithelial barrier severely impedes absorption of orally administered nanoparticles. Herein, we designed ultrasmall PEPT1-targeted gold nanoparticles (GP-AuNPs) using a dual-ligand strategy: Gly-Sar peptides for PEPT1 recognition on intestinal epithelial cells and PEGylation to improve stability and mucus penetration. Orally administered GP-AuNPs efficiently cross the intestinal mucus barrier, undergo specific PEPT1-mediated transcellular absorption in absorptive enterocytes and the follicle-associated epithelium of Peyer’s patches, and enter systemic circulation mainly through the intestine-mesenteric lymph node pathway. Consequently, GP-AuNPs exhibit 41.9-fold higher oral absorption than untargeted PEGylated AuNPs. Importantly, this nanoparticle transport pathway differs from the conventional goblet cell-associated antigen passage pathway for antigen translocation across the intestinal epithelium, as goblet cell uptake does not deliver nanoparticles to the basal side but secretes them back into the lumen with mucus. These findings unravel the PEPT1-mediated oral absorption mechanism of nanoparticles and provide a promising strategy to enhance oral delivery efficiency of nanomedicines.