LNP Formulation Development through Innovative DMTA Technologies

Abstract: Lipid nanoparticles (LNPs) are emerging as a promising modality for addressing unmet medical needs in gene editing and vaccines. However, the rapid growth in discovery activities has outpaced our capacity for designing innovative LNP formulations. To address this, we established a standardized and industry-leading Design-Make-Test-Analyze (DMTA) cycle that includes several significant innovations.
The cost of mRNA and required lipids, combined with the substantial scales required for existing commercial formulation devices, hinders the ability to screen and limits the potential to develop new potent and safe nanoparticle formulations.
To overcome this, we developed a versatile device for miniaturizing LNP formulations with equivalent particle quality to those of commercial benchmark devices. This, in combination with liquid-handling robotics, enabled up to 96 parallel LNP formulations in a single 'one-shot' screening that takes less than 1 minute to complete. We also miniaturized multiple assays of particle physico-chemical characteristics and microscopy-based in vitro cellular assays, enabling an unprecedented level of information on intracellular delivery from limited quantities of screening batch material at very low cost.
The result is a workflow that minimizes material requirements, provides extensive understanding of LNP characteristics and intracellular performance, while simultaneously enabling rapid development cycles at a fraction of the cost. This is applied and supports active AstraZeneca projects, enabling screening of proprietary lipids and targeted ligands. Advanced data modeling enables us to identify formulations from in vitro data that are likely to be inactive in vivo, allowing in vivo resources to be better utilized with LNPs with higher chances of success.