Flexibility-powered Pickering emulsion enhances mucus permeability to alleviate ulcerative colitis

Abstract The physicochemical properties of oral drug delivery carriers significantly influence their interactions with the intestinal barrier, which, in turn, affect their in vivo fate and therapeutic efficacy. As a delivery system with a hierarchical structure and high stability, Pickering emulsions have demonstrated significant advantages in enhancing the bioavailability of encapsulated bioactive compounds. However, the specific role of their inherent flexibility in modulating interactions with the intestinal barrier and influencing delivery efficiency remains poorly understood. In this study, a flexible Pickering emulsion (FPPE) stabilized by chitosan nanoparticles was developed for encapsulating epigallocatechin gallate, aiming to investigate the role and underlying mechanism of its flexible structure in mucus penetration, cellular uptake, and biodistribution in the intestinal tract. Upon reaching the intestinal tissue, FPPE exhibited deformable adaptation, facilitating efficient mucus permeation, prolonged gastrointestinal retention, and enhanced drug absorption. Moreover, FPPE enhanced macrophage uptake and mitochondrial membrane potential, reduced reactive oxygen species scavenging, and triggered macrophage reprogramming. Compared to rigid chitosan microspheres, FPPE more effectively alleviated intestinal inflammation and promoted intestinal barrier repair in a dextran sulfate sodium-induced acute colitis mouse model. This study reveals how Pickering emulsion flexibility facilitates intestinal mucus delivery, guiding their future design and application. Graphical Abstract