Tailored elasticity combined with biomimetic surface promotes nanoparticle transcytosis to overcome mucosal epithelial barrier

Overcoming epithelial barriers to enhance drug absorption is a major challenge for nanoparticle (NP)-based mucosal delivery systems. With adequate physicochemical properties, the transepithelial delivery of NPs may be efficiently enhanced. However, little is known about the role of elasticity on the transport of NPs across the polarized epithelium, especially the processes and mechanisms of endocytosis, intracellular trafficking and exocytosis. In this study, we discovered that zwitterionic hydrogel NPs with varied elasticity displayed considerably different oral insulin absorption on diabetic rats. It was found that NP elasticity strongly shaped the transepithelial behaviors of NPs, and the increase of elasticity boosted the transcytosis by improving both endocytosis and exocytosis. Elasticity also showed a profound effect on the intracellular trafficking routes of NPs, which was closely related to distribution of NPs in exocytosis pathway and their intra-endosome sphere-to-ellipsoid shape transformation. Importantly, NPs with zwitterionic surface experienced more efficient basolateral exocytosis than apical exocytosis, while the elasticity-related exocytosis enhancement appeared to be non-selective. Therefore, tailored elasticity could promote mucosal transcytosis of NPs, which was able to be further improved with biomimetic zwitterionic surface. This study may provide important knowledge for the design of functional nanovehicles to efficiently overcome mucosal epithelial barriers in the future.