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<p>Lipid nanoparticles are a versatile class of clinically approved drug delivery vehicles, particularly for nucleic acid cargoes. Despite this, these materials often suffer from instability issues that limit shelf-life or necessitate storage at ultra-cold temperatures. Herein, we demonstrate that the oxidation of unsaturated hydrocarbons within ionizable lipid tails results in the production of a dienone species that changes the conformation of the lipid tail and generates an electrophilic degradant that reacts with neighboring siRNA cargoes to produce siRNA-lipid adducts. This mechanism highlights the interplay between lipid degradation, colloidal instability, RNA-lipid adduct formation, and loss of bioactivity. In this work, we show that revised drug product matrixes, including mildly acidic, histidine-containing formulations, can improve room temperature stability of siRNA-lipid nanoparticles by mitigating these oxidative degradation mechanisms.</p>

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Buffer optimization of siRNA-lipid nanoparticles mitigates lipid oxidation and RNA-lipid adduct formation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月25日

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  • Daniel A. Estabrook,
  • Lihua Huang,
  • Olivia R. Lucchese,
  • Dylan J. Charland,
  • Zhao Yu,
  • Fareed Bhasha Sayyed,
  • Jonas Y. Buser,
  • Younghoon Oh,
  • Xingyan Liu,
  • Harmon A. Johnson,
  • Kenneth G. Rodriguez,
  • Noah A. Wambolt,
  • Sonia A. Corba,
  • Geoffrey T. Nash,
  • Dennis Yang,
  • Tingting Wang

摘要

Lipid nanoparticles are a versatile class of clinically approved drug delivery vehicles, particularly for nucleic acid cargoes. Despite this, these materials often suffer from instability issues that limit shelf-life or necessitate storage at ultra-cold temperatures. Herein, we demonstrate that the oxidation of unsaturated hydrocarbons within ionizable lipid tails results in the production of a dienone species that changes the conformation of the lipid tail and generates an electrophilic degradant that reacts with neighboring siRNA cargoes to produce siRNA-lipid adducts. This mechanism highlights the interplay between lipid degradation, colloidal instability, RNA-lipid adduct formation, and loss of bioactivity. In this work, we show that revised drug product matrixes, including mildly acidic, histidine-containing formulations, can improve room temperature stability of siRNA-lipid nanoparticles by mitigating these oxidative degradation mechanisms.