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Nano Lett., Apr 19 2024, | https://doi.org/10.1021/acs.nanolett.3c04415
Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles
Jeehae Shin 1,2, Cameron J. Douglas 3,4, Shanwen Zhang 2, Ciaran P. Seath 3, Huan Bao 1,2
1Department of Molecular Physiology and Biological Physics, University of Virginia, 480 Ray C. Hunt Drive, Charlottesville, 22903 Virginia, United States.
2Department of Molecular Medicine, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, 33458 Florida, United States.
3Department of Chemistry, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, 33458 Florida, United States.
4Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, 33458 Florida, United States.
Corresponding Author : Huan Bao
Abstract
mRNA lipid nanoparticles (LNPs) have emerged as powerful modalities for gene therapies to control cancer and infectious and immune diseases. Despite the escalating interest in mRNA-LNPs over the past few decades, endosomal entrapment of delivered mRNAs vastly impedes therapeutic developments. In addition, the molecular mechanism of LNP-mediated mRNA delivery is poorly understood to guide further improvement through rational design. To tackle these challenges, we characterized LNP-mediated mRNA delivery using a library of small molecules targeting endosomal trafficking. We found that the expression of delivered mRNAs is greatly enhanced via inhibition of endocytic recycling in cells and in live mice. One of the most potent small molecules, endosidine 5 (ES5), interferes with recycling endosomes through Annexin A6, thereby promoting the release and expression of mRNA into the cytoplasm. Together, these findings suggest that targeting endosomal trafficking with small molecules is a viable strategy to potentiate the efficacy of mRNA-LNPs.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-04-23)
- 국외 연구진
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