2. Academic Validation
  3. Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles

Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles

  • Nano Lett. 2024 May 1;24(17):5104-5109. doi: 10.1021/acs.nanolett.3c04415.
Jeehae Shin 1 2,  Cameron J Douglas 3 4,  Shanwen Zhang 2,  Ciaran P Seath 3,  Huan Bao 1 2
Affiliations

Affiliations

  • 1 Department of Molecular Physiology and Biological Physics, University of Virginia, 480 Ray C. Hunt Drive, Charlottesville, 22903 Virginia, United States.
  • 2 Department of Molecular Medicine, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, 33458 Florida, United States.
  • 3 Department of Chemistry, UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, 33458 Florida, United States.
  • 4 Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, 33458 Florida, United States.
PMID: 38640421 DOI: 10.1021/acs.nanolett.3c04415
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.

Keywords

Lipid nanoparticles; cellular uptake; endosomal recycling; mRNA; mRNA delivery.

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