Yolk-shell cationic liposomes overcome mucus and epithelial barriers for enhanced oral drug delivery

Liposomes have garnered attention for their potential in oral drug delivery. However, they encounter obstacles when traversing the mucus and epithelial barriers of the gastrointestinal tract. Recent studies indicate that the very characteristics enabling liposomes to penetrate mucus may adversely affect their cellular uptake. In this study, we introduce a novel strategy focused on liposome biomechanical properties, specifically stiffness. Inspired by the stiffness-mediated transformation behaviour of entities like cancer cells in biological environments, we developed yolk-shell structured cationic liposomes (YS-CLip) by incorporating mesoporous silica nanoparticles. Compared to their single-membrane structured counterparts, the YS-CLip demonstrated higher stiffness, adopting an ellipsoidal shape after stress, facilitating rotation-enhanced mucus penetration. This facilitated simultaneous circumvention of mucus diffusion and epithelial absorption barriers. In rats, orally administered YS-CLip adeptly bypassed both mucus and intestinal impediments, leading to an amplified bioavailability of doxorubicin, outperforming both their single-membrane counterparts and certain mucus-penetrating liposomes. Collectively, our findings illuminate the pivotal role of biomechanical stiffness in liposomal formulation, endorsing YS-CLip as a prospective strategy to navigate oral drug delivery challenges.