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
  • 1. Lilly Seaport Innovation Center, Boston, MA, USA. [email protected].
  • 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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