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Orally administered peptides or proteins are garnering increasing preference owing to their superiority in terms of patient compliance and convenience. However, the development of oral protein formulations has stalled due to the low bioavailability of macromolecules that encounter the aggressive gastrointestinal environment and harsh mucus villi barrier. Herein, we propose an ideal reverse micelle/self-emulsifying drug delivery system (RM/SEDDS) nanoplatform that is capable of improving the oral bioavailability of hydrophilic peptides by preventing enzymatic degradation and enhancing mucosal permeability. Upon the passage through the mucus, the self-emulsifying drug delivery system with optimal surface properties effectively penetrates the viscoelastic mucosal barrier, followed by the exposure of the inner reverse micelle amphipathic vectors, which autonomously form continua with the lipidic cell membrane and facilitate the internalization of drugs. This membrane-fusion mechanism inaugurates a new way for hydrophilic peptide delivery in the free form, circumventing the traditional impediments of the cellular internalization of nanocarriers and subsequent poor release of drugs. And more importantly, reverse micelles are not spatially specific to the laden drugs, which enables their delivery for a myriad of peptide clinical drugs. In conclusion, as an exquisitely designed nanoplatform, RM/SEDDS overcomes multiple physiological barriers and opens a new path for drug cellular entry, providing new prospects for the development of oral drug delivery systems.
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