An artistic rendering of lipid nanoparticles showing multiple layers that take on different molecular arrangements, giving the particle varying properties. (Credit: Jenny Nuss)

A collaboration between Lawrence Berkeley National Laboratory and Genentech, a member of the Roche Group, is working to break through drug-delivery bottlenecks by designing effective lipid nanoparticles (LNPs— tiny spherical pouches made of fatty molecules that encapsulate therapeutic agents until they dock with cell membranes and release their contents.

The first drug to use LNPs was approved in 2018, but the delivery method rose to global prominence with the Pfizer and Moderna mRNA Covid vaccines. LNPs are now being widely explored as a delivery system for vaccines for other infectious diseases or therapeutic vaccines for cancer. The viability of these new applications will be dependent on how well the lipid envelopes fuse with target cells, how stable the drug-LNP formulations are in storage (so that they have a long shelf-life), and how stable they are in the body (so they can confer prolonged drug activity).

Scientists at Genentech developed a robot-driven workflow that can generate hundreds of LNP formulations in just a few hours. Samples of each formulation are then brought to Berkeley Lab to perform small-angle x-ray scattering (SAXS) at a circular particle accelerator that creates x-ray beams of different energies.

The biological SAXS beamline can quickly process many samples, and unlike other forms of x-ray diffraction on biological materials, the samples do not need to be frozen or crystalized — which could change the structure of the LNPs and prevent the scientists from discovering what the LNPs would look like at physiological temperatures in the human body. SAXS also allows them to take snapshots of LNPs at a specified timepoints to determine their structural longevity.