Raoul Pullela

Oligonucleotides represent a highly specific drug modality whose power was recently illustrated by the SARS-CoV2 mRNA vaccines. RNA lipid nanoparticle (RNA-LNP) based formulas have been utilised and developed in a variety of other contexts from misfolding diseases, to single-gene disorders to cancer-vaccine design. They can be used for the selective transcript silencing, the knockdown of previously ‘undruggable’ targets, splice modulation and transient gene activation.

Lipid nanoparticles (LNPs) greatly improve the stability and bioavailability of encapsulated oligos, facilitating the expansion of the available drug repertoire. They promote internalisation of LNP cargo into the cell, while reducing systemic toxicity. The manner in which LNPs interface with the body — its nano-bio interactions — are governed by a given particle’s physical and biochemical properties. However, accurately characterising these properties on a single-particle level with high-throughput, remains a challenge. Crucially, unique LNP populations, with similar bulk properties, have shown differences in activity in vivo. The translation of these medicines from the bench-to-bedside has been hampered by poor understanding of the distributions of functionally important properties.

Here at the Knowles’ Lab we aim to characterise LNPs with single particle resolution, and thereby understand the distributions of therapeutic payload encapsulation, LNP size and surface ligands in a given sample using optofluidic microdevices. In this way, we hope to fully dissect and describe the structure-function relationship for LNPs and other lipid-based nanomedicines.