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Synthetic nucleocapsid design
This cutaway view shows the protein design for a synthetic nucleocapsid known as I53-50-v1. (Nature / UW Graphic / Butterfield, Lajoie et al.)

University of Washington researchers have taken a page from the viral playbook to create microscopic assemblies for packaging genetic material — with the goal of using the system for targeted drug delivery.

The assemblies, known as synthetic nucleocapsids, work like viruses to protect their payloads as they enter cells. They can even evolve over time. That may sound like the start of a science-fiction novel, but  the authors emphasize that their plot doesn’t have a scary ending.

“Our nucleocapsids are not viruses, because they have no way to get into cells, out of cells, or replicate on their own without our direct intentional assistance,” they said in an email sent to GeekWire by UW biochemist Marc Lajoie.

Lajoie is one of the authors of the study, published today by the journal Nature.

The team’s molecular packages were designed from the ground up, with proteins unlike those found in the viruses. In this case, each package contained its own RNA genome. The researchers created different varieties of nucleocapsids, injected them into mice, and then extracted blood samples to see how well each variety did.

“This allowed us to evolve properties that will be useful for non-viral targeted drug delivery: improved RNA packaging, resistance to blood, and increased circulation time in living mice,” Lajoie and his colleagues said.

The team built on years of work in protein-building, much of it done at UW’s Institute for Protein Design. As they fine-tuned the packages, they picked up new tricks having to do with molecular architecture.

“We found that a small number of simple mutations allowed surprisingly large improvements for the property under selection, and this trend bodes well for our future attempts to introduce new functions,” Lajoie said in the email sent on the team’s behalf.

For example, the researchers were able to raise the six-hour survival rate for the RNA packages in mouse blood from 3.7 percent to 71 percent, and boost the circulation time from less than 5 minutes to about 4.5 hours.

The next steps will involve tailoring different nucleocapsids to target specific cell types, and tweaking the packages so that they can deliver molecular cargos ranging from small-molecule drugs to RNA, DNA and proteins.

“This could be especially useful for targeted delivery of proteins and mRNAs [messenger RNA molecules], which is a major unmet need in medicine,” Lajoie said.

There’s yet another angle to synthetic nucleocapsids.

“They are the first fully synthetic entities to encapsulate their own genomes and undergo evolution,” the researchers say. “This is exciting, because we were able to design functions that are essential to life without having to use existing cells as a template.”

Lajoie and his colleagues say their work could be “groundbreaking for synthetic life.”

Synthetic life? Now there’s a plot for a science-fiction novel.

Gabriel Butterfield of UW’s Institute for Protein Design and Lajoie are the principal authors of the Nature study, “Evolution of a Designed Protein Assembly Encapsulating Its Own RNA Genome.” Other authors include Heather Gustafson, Drew Sellers, Una Nattermann, Daniel Ellis, Jacob Bale, Sharon Ke, Garreck Lenz, Angelica Yehdego, Rashmi Ravichandran, Suzie Pun, Neil King and David Baker.

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