Nanosyringes from Photorhabdus bacteria, viewed with an electron microscope
Joseph Kratz, Broad Institute of MIT and the McGovern Institute for Brain Research at Harvard, MIT
It may be possible to inject proteins into specific cells in the body thanks to bacterial “nanosyringes” designed to target human cells. This could lead to safer and more effective treatments for a wide range of conditions, including cancer.
When we swallow a pill, the tiny molecules inside spread through the blood to the cells. But because small molecules can easily enter cells, they are not as specific and often have unwanted side effects.
Large molecules such as proteins may have more specific and potent effects than small-molecule drugs. But they cannot cross a cell membrane and enter a cell, making their use very limited. Effective ways to get proteins inside cells in the body could open the door to transformative treatments for a wide range of conditions.
Several groups around the world are attempting to solve this distribution problem, with only limited progress made so far. “Protein delivery has been challenging,” says joseph kratz at the Massachusetts Institute of Technology (MIT).
But bacteria have already solved this problem. Many produce cylindrical structures that bind to cells and forcibly inject their contents into them. “They’re similar to a syringe,” says Kratz.
These nanosyringes resemble phage viruses infecting bacteria, and are likely the result of bacteria co-opting viruses and weaponizing them.
especially, Photorhabdus When the bacteria infect insects, they release nanosyringes filled with toxic proteins. The nanosyringes bind to specific proteins on insect cells and inject toxins into these cells, killing them for the bacteria to feed on.
Kreitz and his colleagues set out to optimize this Photorhabdus Nanosyringes for targeting human cells. They first used the Alphafold AI program to predict the structure of the nanosyringes, including the segment that binds to protein receptors on the outside of cells and triggers injection.
They then changed this segment so that it binds to a human protein called EGFR, which is found on the outside of some cells, again using alphafold to offset the effects of Tweaks. The team showed that this modified nanosyringe could deliver many different types of proteins of varying sizes to human cells containing the EGFR protein.
“The fact that it can load a variety of different payloads of different sizes makes it unique among protein delivery devices,” says Kratz. They say each nanosyringe can hold about 10 proteins, depending on size.
When the nanosyringes were filled with a toxin, they killed cells that contained the EGFR protein but left other cells untouched.
The team leader says, “Target specification is perfect.” Feng Zhang at MIT. “it’s very exciting.”
This suggests that the nanosyringes can be programmed to target any cell type, he says, potentially including various cancers.
The researchers also showed that another nanosyringe, tweaked to target mouse cell surface proteins, could deliver proteins to neurons when injected into the brains of mice. Importantly, however, they have not yet shown that the nanosyringes can deliver proteins to cells after being injected into the bloodstream.
Study shows nanosievings work and approach looks promising, says amin hajitou at Imperial College London, who have modified phage viruses to target human cancer cells. But the team needs to do a lot more work to show that they can be useful for treating disease, he says.
Even if the nanosyringes work when injected into the blood, they can be seen as foreign and trigger the production of antibodies. This is also a problem with virus-based delivery systems used for gene therapy, and means these treatments cannot be given repeatedly over long periods – a major limitation.
However, Kratz says that he has already “decorated” the cylindrical part of the nanosyringe by adding small proteins. They say that in this way it may be possible to separate the nanosyringes from the immune system.
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