Researchers from the McGovern Institute for Brain Research at MIT and the Broad Institute of MIT and Harvard have developed a new protein delivery method using a natural bacterial system. They have successfully programmed this system to deliver various proteins, including gene editing proteins, to different types of cells. This technology has the potential to be a safe and efficient way to deliver gene therapies and cancer treatments.
Led by MIT Associate Professor Feng Zhang, the team utilized a syringe-like injection structure found in a bacterium that naturally injects proteins into insect cells. By using the artificial intelligence tool AlphaFold, the researchers engineered these structures to deliver proteins to both human cells and cells in live mice.
According to Joseph Kreitz, the study’s first author and a graduate student in biological engineering at MIT, this protein engineering technique demonstrates the usefulness of bioengineering and the development of new therapeutic systems. Zhang, the senior author of the study, highlighted the importance of developing new options for delivering therapeutic molecules, as it is currently a major challenge in medicine.
The bacterial injection system, called extracellular contractile injection systems (eCISs), uses a rigid tube inside a sheath that contracts, allowing a spike on the end of the tube to penetrate the cell membrane and deliver protein cargo. By re-engineering the tail fibers of the eCISs, the researchers were able to modify them to target human cells.
Using AlphaFold, the team redesigned the tail fibers to bind to human cells and successfully delivered proteins of their choosing with high efficiency. They specifically targeted cancer cells expressing the EGF receptor and achieved almost 100 percent cell death in these cells while leaving cells without the receptor unaffected. The researchers also delivered proteins to the brains of live mice without any detectable immune response, indicating the potential for safe delivery of gene therapies to humans.
The eCIS system is versatile, allowing for the delivery of various cargoes such as base editor proteins, proteins toxic to cancer cells, and the Cas9 enzyme used in gene editing systems. The researchers are also considering further modifications to the system to deliver other cargoes such as DNA or RNA.
This work was supported by several organizations including the National Institutes of Health, Howard Hughes Medical Institute, and various foundations and centers focused on psychiatric disorders, autism research, molecular therapeutics, and brain-body connections.
In conclusion, the researchers have developed a promising protein delivery system using a natural bacterial system. Their protein engineering approach shows potential for delivering gene therapies and cancer treatments safely and effectively. Further research and development on this system could lead to advancements in the field of medicine.