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

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 and Tingting Wang
Additional contact information
Daniel A. Estabrook: Lilly Seaport Innovation Center
Lihua Huang: Eli Lilly and Company
Olivia R. Lucchese: Lilly Seaport Innovation Center
Dylan J. Charland: Lilly Seaport Innovation Center
Zhao Yu: Eli Lilly and Company
Fareed Bhasha Sayyed: Eli Lilly Services India Pvt Ltd.
Jonas Y. Buser: Eli Lilly and Company
Younghoon Oh: Lilly Seaport Innovation Center
Xingyan Liu: Lilly Seaport Innovation Center
Harmon A. Johnson: Lilly Seaport Innovation Center
Kenneth G. Rodriguez: Lilly Seaport Innovation Center
Noah A. Wambolt: Eurofins Lancaster Laboratories Professional Scientific Services, LLC
Sonia A. Corba: Eurofins Lancaster Laboratories Professional Scientific Services, LLC
Geoffrey T. Nash: Eli Lilly and Company
Dennis Yang: Eli Lilly and Company
Tingting Wang: Eli Lilly and Company

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63651-4

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