2023-04-06| R&D

Re-engineered Bacterial “Syringes” for Programmable Protein Delivery

by Nai Ye Yeat
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The delivery system to ferry potentially therapeutic proteins into human cells is one of the challenges to applying CRISPR in the real medical world. A research team led by Feng Zhang, a pioneer in developing CRISPR, unveiled a new technology of molecular ‘syringe’ that some viruses and bacteria use to infect their hosts.

The novel technique, published in the journal Nature on 29 March, could offer a new way to administer protein-based drugs and modify the current landscape of CRISPR–Cas9 genome editing delivery mechanism.

Related Article: Treating Common Heart Disease with CRISPR-Cas9 Gene Editing

Medical Applications of CRISPR

The lack of a transport system to deliver the DNA-cutting Cas9 enzyme and a short piece of RNA that guides Cas9 to a specific region in the genome into cells limited the use of CRISPR in the clinical stage. 

The current delivery methods restricted most clinical trials to editing genomes in liver, eye, or blood cells, while other diseases, such as brain or kidney diseases, just could not be reached. To tackle this problem, microbiologists seek solutions from mechanisms that bacteria use to bind and pierce a hole in the membranes of host cells.

Endosymbiotic bacteria, which exclusively live in eukaryotic organisms after being engulfed by them, have to deliver factors that modulate host biology in favor of symbiont fitness. That’s why complex delivery mechanisms were developed, extracellular contractile injection systems (eCIS), a class of syringe-like nanomachines resembling bacteriophage tails, is one of them.

Novel Delivery System with High Specificity

The team focused on an eCIS called the Photorhabdus virulence cassette (PVC), which is produced by a bacteria of insects to target their host, deliver a toxin to kill that insect and use the carcass of that insect to facilitate its own reproduction. 

As the PVCs originally target insect cells, human cells will not be recognized in their natural way. Small modifications such as adding a binding domain to the tail fiber could trick the syringe into binding a human cell instead of an insect. With this strategy, high specificity would be expected, and it can also also be applied in killing cancer cells as the PVCs can target cancer epitopes to induce cell death in a very programmable manner with minimal off-target effects.

This re-engineered eCIS could deliver a versatile set of protein payloads beyond toxins, from some very small proteins up to Cas9, which is many times larger than the typical PVC toxin. Scientists also tried to rewire the PVC to load nucleic acids, however, the attempt eventually failed.

To sum up, the study revealed that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy, and biocontrol. And the next step will be trying the technique in a broader tropism, and also investigating the possibility to introduce intravenous delivery.

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