By Jerry Grillo

James Dahlman and Phil Santangelo are helping to define an evolving era in medicine, one in which messenger ribonucleic acid — mRNA — can be delivered directly to cells to fight against disease. And their latest groundbreaking study could clear the way to faster therapeutic discoveries.

Long before the Covid-19 pandemic put a global spotlight on mRNA-based vaccines, these two researchers in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University were combining their distinct skillsets to leverage the clinical potential of mRNA. 

“Our work is very compatible,” said Dahlman, associate professor and McCamish Foundation Early Career Professor. “Phil’s lab designs and manufactures really high-quality mRNA, and my lab develops the lipid nanoparticles to deliver it.”

Therapeutics made from mRNA or DNA hold promise in addressing lots of diseases, explained Santangelo, a professor in Coulter BME, “but they’re not much good if they can’t get where they need to go. If you make cargo, which is essentially what we do in my lab, you need delivery, so James and I have a very natural collaboration.”

Their partnership, which began when Dahlman arrived at Georgia Tech in 2016, consistently yields results published in high-impact journals and garners generous research grants from federal agencies, including the National Institutes of Health (NIH) and the Defense Advanced Research Projects Agency (DARPA). 

That includes a recent flood of cutting-edge papers: two in Nature Biomedical Engineering (from October 2021, and a forthcoming study) as well as their latest publication, released Feb. 7 in Nature Nanotechnology.

“We’re reporting an improved barcoding system that would make animal pre-clinical nanoparticle studies more predictive, speeding up the development of RNA therapies,” Dahlman said.

Several years ago, Dahlman and collaborators developed a technique called “DNA barcoding,” which allows for the rapid, simultaneous screening of many of his custom-made delivery vehicles — what are called lipid nanoparticles, or LNPs. Scientists insert unique snippets of DNA into different LNPs, which are injected into mice. Genetic sequencing is then used to determine which barcodes have reached which specific targets.

The new system described in Nature Nanotechnology takes the screening process a step further. 

“Lipid nanoparticles are usually developed in mice, but when you move them into another species, like a non-human primate — because that’s the natural progression, a primate is more like a human — they frequently don’t work as well,” Santangelo said. “When they don’t, you have to go back and make adjustments.” 

But what if you could streamline the process?

The genes that affect LNP delivery vary between pre-clinical species and humans, though the extent of those differences is unknown because studies comparing nanoparticle delivery across species have been very difficult to perform. Until now. To speed that process, the researchers developed a new testing system they’re calling Species Agnostic Nanoparticle Delivery Screening, or SANDS.

Using SANDS, the team compared nanoparticle delivery simultaneously in mouse, primate, and living human cells, all within specially engineered mice. 

“We can actually put the same group of nanoparticles in all three and compare delivery across species,” Dahlman said. “We found what you might expect: delivery in the primate cells predicted really well how delivery in the human cells would go, whereas the mouse cells were less predictive.”

Unlike the previous barcoding system, which worked well in mouse cells, SANDS needed a different kind of marker for screening, a molecule called reporter mRNA. Santangelo’s lab developed one, “and it basically gets around the limitations of the old system,” he said. “Now we can screen new lipid nanoparticles in mice with primate and human cells.”

SANDS already is facilitating further studies for the research team.

Going forward, Dahlman and Santangelo believe that deeper understanding of the different mechanisms driving delivery in mouse cells and other cells will result in a more efficient selection process for LNPs, making pre-clinical nanoparticle studies more predictive and accelerating the development of RNA therapies.