Tiny 'bacterial syringes' could deliver proteins to individual human cells

"This is a really beautiful example of how protein engineering can alter the biological activity of a natural system."
Mrigakshi Dixit
Representational picture of bacteria.
Representational picture of bacteria.

libre de droit/iStock 

Since the introduction of CRISPR technology in 2013, there has been significant progress in the field of medical science, particularly in cancer research. This has resulted in the development of targeted gene therapies, which employ drugs to target specific genes and proteins to prevent cancer. 

Now, a new advancement uses bacterial "nanosyringes" to deliver protein payloads into individual human tissues and cells.

Nanosyringes to target individual cells

The study is led by researchers from MIT's McGovern Institute for Brain Research and the Broad Institute. 

This new type of "nanosyringe" can attach to human cells and inject customized proteins into them.

For this study, the researchers modified a syringe-like protein found naturally in Photorhabdus asymbiotica, a bacterial species that primarily infects insects. 

It secretes tiny syringes (100 nanometers long), scientifically known as "extracellular contractile injection systems," which can naturally bind to insect cells and inject a protein payload into them to kill them.

“This is a really beautiful example of how protein engineering can alter the biological activity of a natural system," Joseph Kreitz, the study’s first author, a graduate student in biological engineering at MIT, and a member of Zhang’s lab, said in a statement.

The team also used AlphaFold, an artificial intelligence-based program for precisely injecting the protein. This AI program by Google aids in the creation of appropriate protein structures. 

Re-engineered syringe had no negative side effects

In the lab, the re-engineered syringe was tested on mice and human cells. It had no negative side effects on the surrounding cell environment.

Initial results suggest that it could be used to help deliver treatments directly into human cells in the future. According to the release, the syringe can be programmed to deliver a variety of proteins, including those for gene editing as well as can be used for different cell types.

"I think it substantiates protein engineering as a useful tool in bioengineering and the development of new therapeutic systems,” said Kreitz. 

The breakthrough could pave the way for the development of more effective treatments for a variety of diseases, including cancer. Moreover, the innovation could also lead to the development of personalized medicines.

The findings were published in the journal Nature.

Study Abstract:

Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One 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 cellular membrane. Recently, eCISs have been found to target mouse cells raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)—an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica—is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems—including human cells and mice—with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol.

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