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Using Lipid Nanoparticles for the Delivery of Chemically Modified mRNA into Mammalian Cells
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Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery.

Yulia Eygeris1, Michael I Henderson1, Allison G Curtis2

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, 97201, USA.

Small (Weinheim an Der Bergstrasse, Germany)
|May 13, 2024
PubMed
Summary
This summary is machine-generated.

Preformed vesicle lipid nanoparticles (PFV-LNPs) enhance mRNA delivery to the retina, improving retinal tolerability without sacrificing gene editing efficacy. This novel formulation process offers a safer alternative for nucleic acid therapies.

Keywords:
IRDgene deliverylipid nanoparticlemRNAretinal degeneration

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Area of Science:

  • Biotechnology
  • Ophthalmology
  • Gene Therapy

Background:

  • Complete encapsulation of nucleic acids within lipid-based nanoparticles (LNPs) is traditionally considered essential for successful delivery.
  • This encapsulation protects mRNA from degradation and aids in cellular uptake.

Purpose of the Study:

  • To investigate the efficacy of a preformed vesicle lipid nanoparticle (PFV-LNP) approach for mRNA delivery to the retina.
  • To evaluate if superficial mRNA localization in PFV-LNPs impacts delivery efficiency and tolerability compared to traditional LNPs.

Main Methods:

  • PFV-LNPs were formulated using a solvent-free mixing process, resulting in superficial mRNA localization.
  • mRNA delivery and gene editing efficiency were assessed in retinal pigment epithelium and photoreceptors in vivo (mice, non-human primates) and in vitro (human retinal organoids).
  • Retinal tolerability was evaluated in the Ai9 reporter mouse model.

Main Results:

  • PFV-LNPs demonstrated up to a 50% improvement in mRNA delivery to the retina compared to traditional LNPs, despite low encapsulation efficiency.
  • Successful delivery of mRNA and gene editors was observed across multiple species and models.
  • PFV-LNPs achieved comparable gene editing levels to traditional LNPs but showed significantly improved retinal tolerability.

Conclusions:

  • The LNP formulation process critically influences mRNA transfection and gene editing outcomes.
  • PFV-LNPs offer a promising strategy for enhancing the safety of LNP-based nucleic acid therapies for retinal applications without compromising efficacy.