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Antioxidant lipid nanoparticles enhance mRNA stability for regeneration therapy and gene editing

Benhao Li1,2,3, Mengyao Zhao4, Bowei Yang1,2,3

  • 1Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Nature Communications
|June 4, 2026
PubMed

Insights

Researchers developed antioxidant lipid nanoparticles (LNPs) to protect messenger RNA (mRNA) from oxidative damage. These novel antioxidant LNPs improve mRNA stability and therapeutic outcomes in regenerative medicine and genome editing applications.

Area of Science:

  • Biotechnology
  • Molecular Biology
  • Nanomedicine

Background:

  • Messenger RNA (mRNA) therapeutics show promise for various diseases and regenerative medicine.
  • Oxidative stress significantly degrades mRNA, limiting its therapeutic applications.
  • Current lipid nanoparticle (LNP) delivery systems face challenges with mRNA stability under oxidative conditions.

Purpose of the Study:

  • To develop a general strategy for protecting mRNA from oxidative degradation using antioxidant lipids within LNPs.
  • To identify and characterize novel antioxidant ionizable lipids and LNP formulations for enhanced mRNA delivery.
  • To evaluate the efficacy of antioxidant LNPs in preserving mRNA integrity and improving therapeutic outcomes.

Main Methods:

  • Designed and synthesized a library of antioxidant ionizable lipids.
  • Formulated antioxidant lipid nanoparticles (AOLNPs) incorporating a lead antioxidant lipid.
  • Tested AOLNP efficacy in scavenging reactive oxygen species and preserving mRNA integrity under oxidative stress.
  • Assessed protein expression, transcript integrity, and regenerative outcomes in organ and tissue injury models.

Main Results:

  • Identified a lead antioxidant LNP formulation (AO12LNPs) with a 4-hydroxyphenyl-modified antioxidant lipid.
  • Demonstrated that AO12LNPs effectively scavenge reactive species, protecting mRNA from oxidative damage both extracellularly and intracellularly.
  • Showcased sustained high-level, durable protein expression and improved transcript integrity compared to conventional LNPs.
  • Observed enhanced regenerative outcomes and more efficient genome editing in preclinical models.

Conclusions:

  • Antioxidant LNPs offer a robust platform for shielding mRNA from oxidative degradation.
  • AO12LNPs represent a next-generation mRNA delivery system overcoming oxidative challenges in regenerative medicine.
  • This approach holds significant potential for advancing mRNA therapeutics and applications requiring enhanced mRNA stability.

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