As red blood cells zip through vessels, they deliver oxygen to nearly every nook and cranny of your body. But oxygen isn’t all they can tote around. By engineering red blood cells to have “sticky” proteins on their surface, a team of researchers has given the cells the ability to carry anything from drugs to treat immune disorders or cancer to radioactive molecules used in imaging of blood vessels.
“This is really a great idea, and a very novel approach,” says biochemist Vladimir Muzykantov of the University of Pennsylvania, who was not involved in the new work.
Red blood cells account for a quarter of all human cells in the body and survive for an average of 4 months. Their ubiquity and long life makes them an ideal vehicle to carry therapeutics throughout the body, says immunologist Hidde Ploegh of the Massachusetts Institute of Technology in Cambridge. Previously, researchers have loaded red blood cells with drugs by pushing the molecules through the cell’s membrane into its interior, but the process weakens the cell, and the molecules are released only when the cell reaches its final destination.
Ploegh and his colleagues instead wanted to attach molecules to the outside of red blood cells. Because red blood cells don’t have nuclei—and therefore lack genetic material that can be tweaked to make new proteins—the researchers turned to erythroblasts, precursors to red blood cells that still contain DNA. The scientists added to erythroblasts altered versions of genes that are known to encode proteins found on the surface of red blood cells. The introduced gene sequences, though, had modifications so that the erythroblasts produced surface proteins with an extra marker that’s recognized by a protein called sortase.
Those engineered proteins remained as the erythroblasts matured into red blood cells. When the researchers added sortase to the matured cell mixtures, the protein snipped off the ends of any proteins the researchers had genetically modified, leaving “sticky” trailer hitches for cargo. Any molecule with a corresponding sortase tag would then bind to the surface protein on the red blood cell. To show that the hitch would work, Ploegh’s team attached the vitamin biotin to red blood cells and infused them into mice. The biotin-toting cells survived for at least 28 days in circulation and did not harm the mice, they report online today in the Proceedings of the National Academy of Sciences.
Ploegh envisions the technique being used to create a new type of personalized therapy in the future—your own cells could be isolated, used to create stem cells that differentiate into erythroblasts, genetically modified to carry a molecule, and reinjected into your body. Any molecule that needs to be spread through the circulatory system could be the cargo. By the time the cells have matured back into red blood cells, they will have lost their DNA, eliminating the risk of ongoing mutations or the spread of genetic materials. “The payloads you can install are limitless,” Ploegh says. “But a lot of the applications are still, for now, hypothetical.”
Muzykantov, who has developed other approaches for using red blood cells as molecular vehicles, says the significance of the new method “exceeds just drug delivery.” It could be used to track red blood cells to diagnose blood diseases, spread imaging agents throughout the body to visualize atherosclerotic plaques or blocked arteries, or neutralize the immune system before transplants by blocking antibodies that enter the bloodstream.
“But there are lots of questions to address in animal models,” he adds. “I would love to see a demonstration that a real drug binds to a red blood cell using this approach and is still effective.”