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
- Tingting Wang
2025-09-25
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.