Mind the Particle\nRigidity: Blooms the Bioavailability\nvia Rapidly Crossing the Mucus Layer and Alters the Intracellular\nFate of Curcumin

Overcoming intestinal epithelial barriers to enhance\nbioavailability\nis a major challenge for oral delivery systems. Desirable nanocarriers\nshould simultaneously exhibit rapid mucus penetration and efficient\nepithelial uptake; however, they two generally require contradictory\nstructural properties. Herein, we proposed a strategy to construct\nmultiperformance nanoparticles by modifying the rigidity of amphiphilic\nnanostructures originating from soy polypeptides (SPNPs), where its\nability to overcome multibarriers was examined from both <i>in\nvitro</i> and <i>in vivo</i>, using curcumin (CUR)\nas a model cargo. Low-rigidity SPNPs showed higher affinity to mucin\nand were prone to getting stuck in the mucus layer. When they reached\nepithelial cells, they tended to be endocytosed through the clathrin\nand macropinocytosis pathways and further transferred to lysosomes,\nshowing severe degradation and lower transport of CUR. Increased particle\nrigidity generally improved the absorption of CUR, with medium-rigidity\nSPNPs bloomed maximum plasma concentration of CUR by 80.62-fold and\nshowed the highest oral bioavailability. Results from monocultured\nand cocultured cell models demonstrated that medium-rigidity SPNPs\nwere least influenced by the mucus layer and changes in rigidity significantly\ninfluenced the endocytosis and intracellular fate of SPNPs. Those\nwith higher rigidity preferred to be endocytosed via a caveolae-mediated\npathway and trafficked to the ER and Golgi, facilitating their whole\ntranscytosis, and avoiding intracellular metabolism. Moreover, rigidity\nmodulation efficiently induces the reversible opening of intercellular\ntight junctions, which synergistically improves the transport of CUR\ninto blood circulation. This study suggested that rigidity regulation\non food originated amphiphilic peptides could overcome multiple physiological\nbarriers, showing great potential as natural building block toward\noral delivery.