Hierarchical folding of mRNA for cytoplasmic delivery

William Shih

The global response to the Covid-19 pandemic has underscored the vast therapeutic potential for mRNA-vaccine approaches. However, state-of-the-art lipid-delivery vehicles provide only ~1% delivery efficiency for local administration, and formulation at scale requires optimization that is laborious and expensive, and that must be re-done for every mRNA target. Barriers include poor uptake of particles into target cells, poor endosomal escape of engulfed particles, low yields for loading mRNA into lipid particles, limited stability and monodispersity, and the requirement for low-temperature storage. For systemic administration, tissue targeting (outside of liver and spleen) and appropriately long circulation times are challenges that further diminish overall delivery efficiency. Thus there is significant room for improvement. We propose to develop Packaging RNA for Cellular Delivery (PaRCel), a nucleic-acid origami approach for robust delivery of mRNA into the cytoplasm of cells. Our strategy relies on “folding” mRNA into defined nanostructures, similar to traditional DNA origami, followed by coating the structure with peptides that will provide low-salt stabilization, protection from nucleases, and endosomal-escape capabilities. We hypothesize that this platform will provide superior delivery performance, along with more robust stability, storability, and manufacturability, as compared to lipid-nanoparticle approaches. Importantly, the folded nanoparticles can be designed to be compact, with a precisely defined shape and a high volume fraction occupied by the mRNA cargo. Furthermore, folded structures can be decorated in a site-specific fashion, a versatility that can confer functional advantages.

BTIP Agenda

• In-person convening and light dinner: 5:30 – 5:45pm Eastern Time (US and Canada)
• Zoom presentation: 5:45 – 6:45pm Eastern Time (US and Canada)
• In-person networking: 6:45 – 7:00pm Eastern Time (US and Canada)

Contact

For more information about BTIP or to request an invitation, please contact Ifat Rubin-Bejerano, Senior Director of Translational Research.