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In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
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Using Lipid Nanoparticles for the Delivery of Chemically Modified mRNA into Mammalian Cells
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Chirality-Controlled Lipid Nanoparticles for mRNA Delivery.

Juhee Lee1, Wookjin Jung2, Dongkyu Lee2

  • 1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

ACS Applied Materials & Interfaces
|March 17, 2025
PubMed
Summary

Controlling the chirality of lipid nanoparticles (LNPs) enhances messenger RNA (mRNA) delivery. Chiral LNPs improved cellular uptake and mRNA transfection efficiency by over fivefold compared to non-chiral controls.

Keywords:
chiralitycobalt oxide nanoparticlecysteinelipid nanoparticlemRNA delivery

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Area of Science:

  • Biotechnology
  • Materials Science
  • Nanotechnology

Background:

  • Messenger RNA (mRNA) therapeutics offer significant potential for treating human diseases.
  • Effective delivery of mRNA into cells necessitates protective carriers, such as lipid nanoparticles (LNPs).
  • Limited understanding exists regarding how the surface properties of mRNA carriers influence cellular delivery efficiency.

Purpose of the Study:

  • To investigate the impact of chirality on the surface of LNPs for enhanced mRNA delivery.
  • To determine if chiral surface modification of LNPs can improve cellular uptake and transfection of mRNA.
  • To explore the potential of chirality as a strategy for nucleic acid drug delivery.

Main Methods:

  • Preparation of chiral LNPs through surface modification with chiral cobalt oxide nanoparticles.
  • Evaluation of cellular uptake and transfection efficiency of luciferase or EGFP mRNA using d- and l-chiral LNPs.
  • Comparison of chiral LNP performance against control (non-chiral) LNPs.

Main Results:

  • Chiral LNPs exhibited differential cellular uptake and transfection efficiencies based on d- or l-chirality.
  • LNPs functionalized with d-chirality demonstrated a significant enhancement in mRNA cellular delivery.
  • A 5.3-fold increase in mRNA transfection efficiency was observed with d-chiral LNPs compared to control LNPs.

Conclusions:

  • Surface chirality control of LNPs is a viable strategy to enhance mRNA delivery and transfection.
  • Chiral LNPs, particularly those with d-chirality, significantly improve the efficiency of nucleic acid drug delivery.
  • This research deepens the understanding of chirality's role in cellular interactions and drug delivery systems.