The delivery of therapeutic molecules is a major bottleneck for medicine. There is a need for a comprehensive range of options to deliver these powerful new therapies to the right cells in the body.
In a new study, researchers learned how nature transports proteins. Based on that, they came up with a platform to close this gap.
Researchers at the McGovern Institute for Brain Research at MIT and the Broad Institute at MIT and Harvard have developed a new protein delivery strategy that works in both human and animal cells. The system can be programmed to deliver different proteins, such as those used in gene editing, to different cell types. The method could represent a safe and effective approach to cancer and gene therapy delivery.
Researchers used a small syringe-like injection structure produced by a bacterium that naturally binds to insect cells and injects a protein payload into them. Using the AlphaFold AI tool, they developed these syringe structures to deliver various beneficial proteins to both human cells and cells in living mice.
Endosymbiotic bacteria have evolved intricate delivery systems that allow these organisms to interact with host biology. An example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cell membrane.
Tail fibers that detect and latch on to certain receptors on the cell surface are located on the outside of one end of the eCIS. Previous studies have shown that eCISs can naturally target insect and mouse cells. Kreitz hypothesized that it might be possible to modify eCISs to transport proteins into human cells by redesigning the tail fibers to attach to different receptors.
Researchers then used AI to redesign the tail fibers of an eCIS produced by Fotorhabdus bacteria to bind to human cells. This re-engineering allows scientists to trick the syringe into delivering a protein of choice, in some cases with remarkably high efficiency.
The researchers created eCISs that specifically targeted cancer cells expressing the EGF receptor and showed that they almost completely eliminated the target cells while having little effect on cells lacking the receptor. Despite the fact that the effectiveness partly depends on the receptor that the system should target.
The researchers also used an eCIS to safely transfer proteins to the brains of live mice, and they found that this method did not trigger any immune responses. This suggests that eCISs could one day be used to deliver gene treatments to people without risk.
Joseph Kreitz, the study’s first author, a graduate student in biological engineering at MIT, and a member of Zhang’s lab, said: “The eCIS system is versatile and the team has already used it to deliver a range of payloads, including basic editor proteins (which can make one-letter changes to DNA), proteins that are toxic to cancer cells, and Cas9, a large DNA-cutting enzyme used in many gene-editing systems.”
“In the future, researchers could develop other components of the eCIS system to tune other properties or deliver other payloads such as DNA or RNA. He also wants to better understand the function of these systems in nature.”
“We and others have shown that this type of system is incredibly diverse in the biosphere, but they are not very well characterized. And we believe that this type of system plays an important role in biology that has yet to be explored.
- Kreitz, J., Friedrich, MJ, Guru, A. et al. Programmable protein delivery with a bacterial contractile injection system. Nature (2023). DOI: 10.1038/s41586-023-05870-7