Coumaric acid (CA) is a typical nutrient required in relatively high quantities by the body. It has been proved CA could specifically bind to monocarboxylate Transporter-1 (MCT-1) receptors, a transporter protein expressed on the surface of intestinal epithelial cells, to facilitate its cellular uptake. Although our preliminary research demonstrated semaglutide (SEM) loaded CA modified nanoparticles (SEM@CNP) could improve the absorption of SEM to some extent, the oral bioavailability still remained suboptimal owing to the lysosomal degradation. To address this issue, INF-7 (peptide chain GLFEAIEGFIENGWEGMIDGWYG) and chloroquine (CQ), two lysosomal escape agents (LEAs) with different mechanisms of action, were incorporated with SEM@CNP for oral delivery (SEM@CNP + INF-7, SEM@CNP + CQ). In type II diabetes mice models, SEM@CNP + CQ effectively inhibited postprandial glucose rise with a relative pharmacological bioavailability of 20.63 ± 2.99 %, 1.73 times higher than SEM@CNP (11.90 ± 4.56 %). Mechanistic studies revealed that: 1) after adding LEAs, the exocytosis preference of nanoparticles was altered, tending towards basolateral exocytosis apparently. Regulated exocytosis directionality was linked to the spatial redistribution of MCT-1 receptors. 2) among the two LEAs, CQ demonstrated superior efficacy compared to INF-7. This superiority was attributed to the earlier onset of action and more pronounced degree of membrane disruption induced by CQ. This research provided new insights for the design of oral delivery systems for peptidic drugs.
