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Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles

Jeremy P Bost1, Hanna Barriga2, Margaret N Holme2

  • 1Department of Laboratory Medicine, Karolinska Institutet, Huddinge 14152, Sweden.

ACS Nano
|September 10, 2021
PubMed

Insights

Oligonucleotides (ONs) are promising therapeutics, but cellular delivery is challenging. This review explores methods like chemical modification, lipid nanoparticles, and extracellular vesicles to improve ON endosomal escape for better therapeutic efficacy.

Area of Science:

  • Biotechnology
  • Molecular Biology
  • Drug Delivery

Background:

  • Oligonucleotides (ONs) are a rapidly expanding class of therapeutics targeting DNA and RNA.
  • Despite recent FDA approvals, ONs face challenges with cellular internalization and endosomal escape.
  • Effective delivery to the cytosol or nucleus is crucial for ON therapeutic action.

Purpose of the Study:

  • To review the design and action of FDA-approved ON therapies.
  • To classify common ON types and chemical modifications.
  • To explore strategies for enhancing ON cellular delivery and endosomal escape.

Main Methods:

  • Review of existing literature on oligonucleotide therapeutics and delivery mechanisms.
  • Analysis of cellular uptake pathways for ONs.
  • Focus on three key delivery strategies: chemical modification, lipid nanoparticles, and extracellular vesicles.

Main Results:

  • Discussion of fundamental scientific principles behind various ON classifications and modifications.
  • Mapping of cellular trafficking pathways relevant to ONs.
  • Highlighting recent advancements in ON delivery approaches.

Conclusions:

  • Endosomal escape remains a critical hurdle for oligonucleotide therapeutics.
  • Chemical modifications, lipid nanoparticles, and extracellular vesicles show promise for improving ON delivery.
  • Further research into these strategies is essential for advancing ON-based therapies.
Keywords:
RNA therapeuticscellular uptakeendosomal escapeextracellular vesiclesintracellular traffickinglipid nanoparticlesoligonucleotideoligonucleotide delivery

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