By Kristopher Benke
Colin McKinlay originally came to the Foundry on behalf of Nutcracker Therapeutics to learn more about peptoids—short amino acid chains similar to peptides but with expanded tunability that makes them ideal for drug delivery applications. At the Foundry, he worked with staff scientist and peptoid-pioneer Ron Zuckerman to find a way to use these molecules to deliver mRNA to specific targets in the body. Now Nutcracker Therapeutics has its own peptoid-based delivery platform which it uses to help enable personalized cancer therapeutics.
Tell me a little about Nutcracker Therapeutics. How was it founded and what kind of work do you do?
Nutcracker Therapeutics is an mRNA based therapeutic development and manufacturing company. What that means is that we take the same general platform of technology that’s in the COVID vaccines but then apply it to other types of applications.
One of the main ones that we’re working on is personalized cancer therapeutics, so basically vaccinating your cells to fight off the cancer that you specifically have. That means your drug and my drug are going to look slightly different because the cancer that you might develop could be a little bit different and specific to you.
Nutcracker was founded back in 2018 by two people out of the semiconductor industry–not actually people with backgrounds in therapeutics–but one of the key founding principles around the company was the limitations of manufacturing these types of therapeutics. What they wanted to do was to take some of the learnings that came from the semiconductor manufacturing industry and apply them to these mRNA-based drugs.
What question did you originally come to the Foundry to answer? What made the Foundry the right place to begin your investigation?
My group at Nutcracker specifically works on our nanoparticle delivery approach, which packages the mRNA and enables it to reach its intended destination in the body. That’s really where we took advantage of some of the expertise and resources at the Molecular Foundry, specifically to learn more about the molecules used in that packaging process.
To do this packaging, you need to set up molecules that can hold onto the mRNA molecule and incorporate it into that particle. So the founders of the company and I got connected with Ron Zuckerman—now Researcher Emeritus at the Foundry—who is a pioneer of a class of molecules called peptoids that mimic the functionality of proteins. They’re sequence specific, like a peptide is, but they have a lot more diversity that you can incorporate onto their side chains. You’re not limited by the standard set of twenty amino acids–you can access nearly all of chemical space to add different types of functionality.
And so we asked the question, would peptoids themselves be a useful platform for us to develop as the encapsulating molecules in these liquid nanoparticles? Could this be the active component that holds on to the mRNA and both shields it from degradative enzymes in the body, and then helps release it once it gets to its target?
When we got connected with Ron, it flowed naturally that there were all of these resources up at the Molecular Foundry and Berkeley Lab, specifically set up to make these peptoid molecules more accessible to a range of different scientists and startups.
Where did you start? How did you go about finding peptoids that would do what you wanted?
The first phase of the project was really a screening type exercise where we would make 20, 30, 40 different peptoids, and then we would test them for their ability to deliver mRNA. We would encapsulate mRNA in them and then either treat cells in a dish with that formulation or introduce them into an animal model and see if we could have that mRNA be expressed. That was the first phase where we were really just trying to find what peptoids worked and what about the structure makes them work.
Once we had a better idea of which peptoids worked, the second phase was taking the other microscopy and biophysical analysis techniques that are available at the Foundry and applying those to our lead candidates and learning more about the biological and physical mechanisms that cause them to work.
As you learned more about how the peptoids work, how did your project grow and evolve in your time at the Foundry?
When we first started, Nutcracker was a very small operation, and we didn’t have a lot of chemistry resources, and so our first user proposal was really set up around the idea of “let’s make a small number of these peptoid-like molecules and start to learn what properties might make them effective for delivering mRNA molecules.”
That ballooned into follow-up proposals that were looking at more specific aspects of the peptoids, and that has been the foundation of the great relationship that we’ve built with the Foundry over the last seven or eight years now.
More recently, we have built up some of those capabilities–we can make peptoids at our location now, and that’s meant that the focus of our work with the Foundry has morphed into characterization and understanding the properties of the peptoids that we have.
What was very cool to see is how flexible the Foundry was about allowing the project to take different forms as our needs changed. They’ve consistently been willing to adjust the arrangement and explore different types of proposals as we’ve grown and scaled.
How would you say your time at the Foundry has impacted Nutcracker Therapeutics in the long term?
I don’t think it’s hyperbole to say that we wouldn’t have been able to put together the delivery program that we did without having the Molecular Foundry available to us so early. It just enabled us to iterate and test and screen things at such a higher rate than if we had to rely on more traditional outsourcing or contract manufacturing—I just don’t think it would have happened in the same way. We may have ended up licensing someone else’s delivery technology instead of going through the effort to develop our own.
I hope I’m not overstating that, but it truly has been, especially at the beginning, an incredibly crucial resource in getting us going.
The delivery aspect of what Nutcracker does is one of our core competencies that we work on at the company. It’s not the only thing that we do, obviously, but it’s one of the key things that we see as differentiating for the company compared to other people that are out there. That’s been rewarding for me, and then really an interesting project scientifically.
