Dense surface coverage of nanocarriers with hydrophilic and uncharged poly(ethylene glycol) (PEG) is one of the most efficient strategies to increase their transport in the mucus barrier. However, this approach is not exempt of criticism, namely with regard to the interaction of PEGylated nanosystems with cell membranes and fate once inside the cells. This project aims at developing stimulus-sensitive cleavable PEG-coated (commonly referred to as PEGylated) mucus-penetrating nanocarriers for the effective local delivery of IBD drugs. The mucus-penetrating behavior of nanocarriers yielded by surface modification with PEG aims to trigger an efficient transposition of the mucus barrier. The cleavable behavior of the PEGylation in response to microenvironmental ROS overexpressed in the inflamed epithelium of gastrointestinal tract fits two main purposes. First, the shedding of the PEG layer will limit the transport of nanocarriers back towards the mucosal lumen once near the epithelium. Second, the hydrophobic and/or charged surface presented by de-PEGylated NPs will maximize the interaction of nanocarriers with target cells and tissues underlying mucus.