Mechanistic Modeling of Lipid Nanoparticle Formation for the Delivery of Nucleic Acid Therapeutics

TL;DR

This paper discusses the development of mechanistic models to understand and optimize the formation of lipid nanoparticles for nucleic acid delivery, aiding process scale-up and quality control.

Contribution

It introduces strategies for modeling LNP formation at multiple scales, linking physicochemical properties to process control and product quality.

Findings

Models predict key physicochemical properties of LNP components

Framework links process parameters to nanoparticle quality attributes

Guides development of advanced process control strategies

Abstract

Nucleic acids such as mRNA have emerged as a promising therapeutic modality with the capability of addressing a wide range of diseases. Lipid nanoparticles (LNPs) as a delivery platform for nucleic acids were used in the COVID-19 vaccines and have received much attention. While modern manufacturing processes which involve rapidly mixing an organic stream containing the lipids with an aqueous stream containing the nucleic acids are conceptually straightforward, detailed understanding of LNP formation and structure is still limited and scale-up can be challenging. Mathematical and computational methods are a promising avenue for deepening scientific understanding of the LNP formation process and facilitating improved process development and control. This article describes strategies for the mechanistic modeling of LNP formation, starting with strategies to estimate and predict important physicochemical properties of the various species such as diffusivities and solubilities. Subsequently, a framework is outlined for constructing mechanistic models of reactor- and particle-scale processes. Insights gained from the various models are mapped back to product quality attributes and process insights. Lastly, the use of the models to guide development of advanced process control and optimization strategies is discussed.