Molecular Dynamics-Guided Sterol Engineering of mRNA-Lipid Nanoparticles Reprograms Biodistribution and Enhances...

Area of Science:

• Biotechnology and Nanomedicine
• Drug Delivery Systems
• Immunology

Background:

• The membrane composition of mRNA-lipid nanoparticles (LNPs) influences their performance.
• Sterols are crucial LNP components, but less explored than ionizable lipids.
• Understanding sterol structure-property relationships is key for LNP optimization.

Purpose of the Study:

• To engineer and evaluate bile acid-derived sterols for mRNA-LNP formulations.
• To correlate sterol structure with LNP physicochemical properties and in vivo expression.
• To assess the immunological impact of sterol modification in LNPs.

Main Methods:

• Synthesized nine bile acid-derived sterols with varied structures.
• Performed physicochemical characterization and all-atom molecular dynamics (MD) simulations.
• Evaluated LNP formulation, organ-level expression, and immune responses in vivo.

Main Results:

• Sterol structure dictates LNP membrane organization and mRNA encapsulation efficiency.
• Bile acid-derived sterols shifted LNP expression from liver to spleen.
• CA-20 LNPs enhanced antigen-specific humoral and cellular immunity, including memory responses.

Conclusions:

• Sterol engineering is a potent strategy for modulating LNP properties and function.
• Bile acid-derived sterols offer a promising alternative to cholesterol for LNP development.
• Optimized sterols can enhance vaccine efficacy and immune memory while ensuring safety.