The use of lipid nanoparticles (LNPs) for the in vivo delivery of RNA payloads in a variety of applications produced promising results including the recent FDA approval of the first-ever RNAi drug, Onpattro™ (Patisiran). Despite this success, most LNPs still tend to accumulate in the liver. Yet, previous studies have indicated the importance of including targeting moieties to reach non-hepatic tissues. In this ERC project, we demonstrate the successful incorporation of a targeting moiety in a unique, cell-specific LNP that recognize a defined population of gut-homing leukocytes involved in Inflammatory Bowel Diseases (IBD). Our targeting strategy is sensitive to the conformational state of the targeted receptor and enables a selective targeting of therapeutic payloads and molecular imaging approaches to better control and manage IBD.