Smart Supramolecular Core–Shell Aggregates with Mucin‐Triggered Surface Switch for Effectively Overcoming Contradictory Mucus and Epithelium Barriers

Rapid mucus permeation and fast epithelium uptake are essential yet paradoxical requirements for efficient oral nanocarriers. For example, hydrophilic and electroneutral surfaces favor fast muco‐penetration, but hydrophobic and positively charged surfaces facilitate epithelial internalization. Mucoinert yet cell membrane high‐affinity nanocarriers will simultaneously achieve effective mucus diffusion and epithelial endocytosis, but their fabrication is generally complex, such as introducing cationic and anionic groups via a synthetic method. Herein, a facile non‐covalent synthetic method for core–shell supramolecular aggregates (HPMC@PC) with mucin‐triggered surface hydrophilic‐to‐hydrophobic transition is engineered through a hydrogen bonding‐driven self‐assembly approach utilizing hydroxypropyl methylcellulose (HPMC) and soybean lecithin (PC). It is demonstrated that HPMC/PC molar ratios can be used to tune the hydrophilic shell thickness. HPMC@PC with a moderate shell thickness exhibits hydrophilicity during mucus diffusion to promote rapid muco‐permeation but exactly switches to hydrophobicity upon arriving at the epithelial surface for facilitating subsequent cellular internalization, thus achieving drug release at targeted intestinal segments with corresponding mucus depth. HPMC@PC exhibits potent delivery ability in a mucus‐covered Caco‐2 monolayer model and in orally administered rats, compared to bare (nano‐PC) and covalently modified HPMC nanoparticles (HPMC‐PC). This study showcases a paradigm of engineering stimuli‐responsive supramolecular aggregates overcoming contradictorily cascaded barriers encountered during drug delivery.