Berkeley Lab and Genentech have partnered to design the next generation of lipid nanoparticles (LNPs), an emerging drug delivery technology used in the COVID-19 vaccines. These tiny spherical structures, which are made of fatty molecules, effectively encase therapeutic agents and deliver them unscathed to affected tissues. As the research world explores the wide-ranging uses for LNPs, their viability for different applications will depend on their ability to fuse with target cells, remain stable, and provide prolonged drug activity in the body.
A team co-led by Greg Hura and Michal Hammel, both biophysicist staff scientists in the Molecular Biophysics & Integrated Bioimaging Division, and Chun-Wan Yen, senior principal scientist in Genentech’s Small Molecule Pharmaceutical Sciences group, has studied how to tune the structure of LNPs for these desired properties for several years. Leveraging expertise in structural biology and pharmaceutical science, the team has devised a high-throughput workflow to rapidly produce and analyze LNPs. Genentech’s robot-driven system quickly generates a high volume of LNP formulations that are then analyzed using small-angle X-ray scattering (SAXS) at the Advanced Light Source, screening potential LNP formulations at an unprecedented rate. The SAXS technique also allows researchers to examine LNPs’ structures without freezing or crystallizing the samples, providing a better understanding of how they might behave over time in the human body.
The team’s latest study, published in ACS Nano, employs their accelerated method and large datasets to present the first-ever demonstration of how LNP structure interacts with the activity of its contents. By studying LNPs loaded with antisense oligonucleotides (small snippets of RNA or DNA base pairs that block gene expression), the team discovered that LNPs with well-ordered internal structures achieved better silencing of a faulty gene associated with a degenerative disease.
The researchers propose this methodology as a general technique for optimizing lipid nanoparticles which could be applied to vaccines, cancer therapeutics, and beyond. Future experiments will focus on understanding the impact of ingredient concentration and production methods on LNP activity and their interactions with diverse target cells and cargo types.