Review of machine learning for lipid nanoparticle formulation and process development.

Lipid nanoparticles (LNPs) are a subset of pharmaceutical nanoparticulate formulations designed to encapsulate, stabilize, and deliver nucleic acid cargoes in vivo. Applications for LNPs include new interventions for genetic disorders, novel classes of vaccines, and alternate modes of intracellular delivery for therapeutic proteins. In the pharmaceutical industry, establishing a robust formulation and process to achieve target product performance is a critical component of drug development. Fundamental understanding of the processes for making LNPs and their interactions with biological systems have advanced considerably in the wake of the COVID-19 pandemic. Nevertheless, LNP formulation research remains largely empirical and resource intensive due to the multitude of input parameters and the complex physical phenomena that govern the processes of nanoparticle precipitation, self-assembly, structure evolution, and stability. Increasingly, artificial intelligence and machine learning (AI/ML) are being applied to improve the efficiency of research activities through in silico models and predictions, and to drive deeper fundamental understanding of experimental inputs to functional outputs. This review will identify current challenges and opportunities in the development of robust LNP formulations of nucleic acids, review studies that apply machine learning methods to experimental datasets, and provide discussion on associated data science challenges to facilitate collaboration between formulation and data scientists, aiming to accelerate the advancement of AI/ML applied to LNP formulation and process optimization.