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Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics
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Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics
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Journal Article
Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics
2021
Overview
The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles are one of the most advanced non-viral clinically approved nucleic-acid delivery systems. Yet lipid nanoparticles 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 conformation of α4β7 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 lipid nanoparticles did not induce adverse immune activation or liver toxicity. These results suggest that our lipid nanoparticle targeting strategy might be applied for selective delivery of payloads to other conformation-sensitive targets.While targeted lipid nanoparticles might allow partial delivery of genetic materials to non-hepatic cells, the selectivity of this approach is still unsatisfying. Here the authors functionalize their lipid nanoparticles with a targeting moiety that recognizes a protein conformation specific to gut-homing leukocytes, inducing gene silencing exclusively in this cellular subset and providing a potential therapeutic strategy for inflammatory bowel disease.
