The rising global prevalence and socio-economic impact of Inflammatory Bowel Disease (IBD) highlight the pressing demand of innovative solutions. Drug-targeting technologies are urgently needed to effectively deliver drugs directly to the affected areas of the gastrointestinal tract (GIT). In this work, a surface-tunable nanosystem responsive to reactive oxygen species (ROS) was developed for the focal oral delivery of budesonide to IBD affected GIT areas. Poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were functionalized with a dense hydrophilic polyethylene glycol (PEG) corona linked by a ROS-sensitive moiety to obtain cleavable PEG (CleavPEG) NPs. CleavPEG NPs with nearly 100 nm and high association efficiency ( approximately 70 %) presented an oxidation-responsive in vitro release of budesonide highly associated (> 60 %) with epithelial intestinal cells and macrophages without decreasing cell metabolic activity. In an inflamed 3D intestinal model, budesonide association to NPs allowed for minimal permeation of budesonide, when compared to its free form, with a similar reduction of IL-8, CXCL10/IP-10 and CCL20/MIP3a. Moreover, in a DSS-induced colitis mice model, CleavPEG NPs accumulated more in the colon than PEG NPs without cleavable linker, and repeated oral treatment with budesonide-loaded CleavPEG NPs decreased intestinal inflammation: confirmed by colonoscopy and quantified by a disease activity index (DAI) and levels of pro-inflammatory cytokines in colon comparable to healthy animals. CleavPEG NPs were efficiently responsive to oxidative environment, and improved budesonide efficacy in resolving inflammation, showing promise for the treatment of IBD.