Conformation Sensitive Targeting of Lipid Nanoparticles for RNA Therapeutics

The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles (LNPs) are one of the most advanced, non-viral clinically approved nucleic-acid delivery systems. Yet, LNPs accumulate naturally in liver cells upon intravenous administration and hence there is an urgent need to enhance uptake by other cell types. Here we use a conformation-sensitive targeting strategy to achieve in vivo gene silencing in a selective subset of leukocytes and show potential therapeutic applications in a murine model of colitis. In particular, by targeting the high-affinity (HA) conformation of α(4)β(7) integrin, which is a hallmark of inflammatory, gut-homing leukocytes, we silenced interferon γ in the gut resulting in an improved therapeutic outcome in experimental colitis. The LNPs did not induce adverse immune activation or liver toxicity. These results suggests that our LNP targeting strategy might be applied for selective delivery of payloads to other conformation-sensitive targets.