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Glucagon\u2010like peptide\u20102 (GLP\u20102) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP\u20102 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD\u2010targeted nanoparticles (NPs) for the oral delivery of the GLP\u20102 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS\u2010sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de\u2010PEGylation is possible by including a ROS\u2010sensitive thioketal linker within the system. ROS\u2010sensitive NPs are established, with the ability to fully de\u2010PEGylate via ROS\u2010mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis\u2010induced mice, ROS\u2010sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.<\/jats:p>","DOI":"10.1002\/smll.202402502","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T05:57:31Z","timestamp":1721023051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Orally Delivered Stimulus\u2010Sensitive Nanomedicine to Harness Teduglutide Efficacy in Inflammatory Bowel Disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Andreia S.","family":"Barros","sequence":"first","affiliation":[{"name":"i3S\u2010Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto  Porto 4200\u2010135 Portugal"},{"name":"ICBAS\u2010 Instituto Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto  Porto 4050\u2013313 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