2. Academic Validation
  3. Buffer optimization of siRNA-lipid nanoparticles mitigates lipid oxidation and RNA-lipid adduct formation

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

  • Nat Commun. 2025 Sep 25;16(1):8380. doi: 10.1038/s41467-025-63651-4.
Daniel A Estabrook 1,  Lihua Huang 2,  Olivia R Lucchese 3,  Dylan J Charland 3,  Zhao Yu 2,  Fareed Bhasha Sayyed 4,  Jonas Y Buser 2,  Younghoon Oh 3,  Xingyan Liu 3,  Harmon A Johnson 3,  Kenneth G Rodriguez 3,  Noah A Wambolt 5,  Sonia A Corba 5,  Geoffrey T Nash 2,  Dennis Yang 2,  Tingting Wang 2
Affiliations

Affiliations

  • 1 Lilly Seaport Innovation Center, Boston, MA, USA. estabrook_daniel@lilly.com.
  • 2 Eli Lilly and Company, Indianapolis, IN, USA.
  • 3 Lilly Seaport Innovation Center, Boston, MA, USA.
  • 4 Eli Lilly Services India Pvt Ltd., Bengaluru, India.
  • 5 Eurofins Lancaster Laboratories Professional Scientific Services, LLC, Lancaster, PA, USA.
PMID: 40998813 DOI: 10.1038/s41467-025-63651-4
Abstract

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.

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