The combination of endolysosomal escape and basolateral stimulation to overcome the difficulties of “easy uptake hard transcytosis” of ligand-modified nanoparticles in oral drug delivery

(3.6-fold or 4.1-fold higher than that of free insulin). Inspiringly, the simultaneous addition of the abovementioned two chemicals led to the highest transcytosis efficiency of insulin, which was up to 5.1-fold higher than that of free insulin. These results demonstrated that endolysosomal entrapment and basolateral exocytosis are two of the most important limiting steps for the "easy uptake hard transcytosis" of orally administered ligand-modified NPs. Moreover, our work provides a new point of view for the design of novel oral drug delivery systems.