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.
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We thank V. Holdengreber for assistance with the transmission electron microscopy analysis, P. Johnston for detailed statistical analysis of the molecular imaging part, S. Chatterjee for help with the confocal microscope and S. Jung for providing the IL-10KO mice. This work was supported by the ERC grant LeukoTheranostics (award no. 647410) to D.P.
D.P. receives licensing fees (to patents on which he was an inventor) from, invested in, consults (or on scientific advisory boards or boards of directors) for, lectured (and received a fee) or conducts sponsored research at TAU for the following entities: Alnylam Pharmaceuticals Inc. Arix Biosciences Inc., ART Biosciences, BioNtech RNA pharmaceuticals; Centricus, Diagnostear Ltd., EPM Inc., Earli Inc., lmpetis Biosciences, Kernal Biologics, GPCR Inc., Medison Pharma Ltd., Newphase Ltd, NLC Pharma Ltd., Nanocell Therapeutics, NanoGhosts Ltd., Precision Nanosystems Inc., Paul Hastings Inc., Regulon, Roche, SciCann, Shire Inc., VLX Ventures, TATA Cooperation, Teva Pharmaceuticals Inc., Wize Pharma Ltd. All other authors declare no competing financial interests. None of them relates to this work. The rest of the authors declare no financial interests.
Peer review information Nature Nanotechnology thanks Monica Baiula, JianFeng Chen, Yizhou Dong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Dammes, N., Goldsmith, M., Ramishetti, S. et al. Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics. Nat. Nanotechnol. 16, 1030–1038 (2021). https://doi.org/10.1038/s41565-021-00928-x
Nature Medicine (2021)
Communications Biology (2021)