Mucus is a viscoelastic
biological hydrogel that protects the epithelial
surface from penetration by most nanoparticles, which limits the efficiency
of oral drug delivery. Pursuing highly efficient, biocompatible, and
biodegradable oral drug vehicles is of central importance to the development
of promising nanomedicine. Here, we prepared five peptosomes (PSs)
with various sizes, shapes, and rigidities based on self-assembly
of amphiphilic α-lactalbumin (α-lac) peptides from partial
enzymolysis and cross-linking. The mucus permeation of α-lac
PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated.
Compared with a long nanotube, big nanosphere, small nanosphere, and
cross-linked short nanotube, we demonstrated that a short nanotube
(SNT) exhibits excellent permeability in mucus, which enables it to
arrive at epithelial cells quickly. Besides, SNT exhibits the highest
cellular uptake and transmembrane permeability on Caco-2/HT29-MTX
(E12) 3D coculture model. In vivo pharmacokinetic evaluation
revealed that SNT formulation shows the highest curcumin
bioavailability, which is 6.85-folds higher than free Cur. Most importantly,
Cur loaded in SNT exhibits the optimum therapeutic efficacy for in
vivo treatment of dextran sulfate sodium (DSS)-induced ulcerative
colitis. In the end, the mechanism of the high permeability of SNTs
through mucus was explained by coarse-grained molecular dynamics simulations,
which indicated that short time scale jiggling and flying across pores
of mucus network played key roles. These findings revealed the tubular
α-lac PSs could be a promising oral drug delivery system targeted
to mucosal for improving absorption and bioavailability of hydrophobic
bioactive ingredients.