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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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Increased PIP3 activity blocks nanoparticle mRNA delivery.

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  • 1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.

Science Advances
|August 4, 2020
PubMed
Summary
This summary is machine-generated.

Altering cell metabolism with phosphatidylinositol (3,4,5)-triphosphate (PIP3) unexpectedly blocked messenger RNA (mRNA) delivery via lipid nanoparticles (LNPs). This finding impacts nanoparticle drug delivery strategies by revealing metabolic pathway interference.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Drug Delivery Systems

Background:

  • Biological pathways influencing in vivo drug delivery are not fully understood.
  • Phosphatidylinositol (3,4,5)-triphosphate (PIP3) is a bioactive lipid regulating the PI3K/AKT/mTOR pathway involved in cell growth and proliferation.

Purpose of the Study:

  • To investigate if modulating cell metabolism with PIP3 could enhance protein translation from nanoparticle-delivered mRNA.
  • To determine the effect of PIP3 on the delivery efficiency of lipid nanoparticles (LNPs).

Main Methods:

  • In vitro and in vivo experiments using various cell types.
  • Treatment with PIP3 to alter cell metabolism.
  • Analysis of LNP delivery, cell uptake, endosomal escape, and toxicity.
  • RNA sequencing and metabolomics analyses.
  • Assessment of transcriptional activity and mitochondrial morphology.

Main Results:

  • PIP3 unexpectedly blocked the delivery of clinically relevant LNPs in multiple cell types, both in vitro and in vivo.
  • Reductions in LNP delivery were not attributed to toxicity, reduced cell uptake, or impaired endosomal escape.
  • Metabolomic and transcriptomic data indicated an increased basal metabolic rate, heightened transcriptional activity, and mitochondrial expansion.

Conclusions:

  • PIP3 interferes with LNP-mediated mRNA delivery, contrary to initial hypotheses.
  • Two potential mechanisms for reduced LNP delivery include resource competition ('drowning out' mRNA) or a catabolic response leading to protein degradation.
  • Findings suggest that metabolic state significantly impacts nanoparticle-based drug delivery efficacy.