Hijacking bacterial syringes for drug delivery

TLDR: Scientists hijack a bacterial injection system to better deliver protein drugs

Bacteria aren’t all bad. They help us digest food, fight infection, and gave us mitochondria (the powerhouse of the cell!!!). They have many useful evolutionary skills that we can learn from and copy.

One such skill is how to inject proteins into cells. This is surprisingly hard to do and something we struggle with in drug delivery. Some bacteria have a syringe-like system for delivering proteins through the cell membrane, directly into the cell.

Today, we’ll learn how scientists hijacked this syringe system and made it into a new drug delivery technology.

The Study: Programmable protein delivery with a bacterial contractile injection system

Big Takeaways

1. Bacteria use syringe-like injection systems to deliver proteins into cells.

2. The syringes recognize a specific cell type, drive a spike through the cell membrane, then release their protein cargo.

3. Scientists modified the syringes to load desired protein drugs and recognize human cells.

4. Hijacked bacterial syringes are highly specific and efficient delivery vehicles for both cancer therapy and gene-editing proteins.

You have about 100 trillion bacteria living in your digestive system right now that help you break down food, stay healthy, and even communicate with your brain. In fact, you have around 10x more bacterial cells in your body than human cells.

Sometimes all bacteria want to do is live in peace with their host. However, to do this they occasionally need to be a bit aggressive. They often release proteins that let the host (aka you) tolerate their presence.

It’s not enough to just create some proteins. The bacteria have to get these proteins inside of the host cells for them to work. And the proteins don’t go in by themselves.

Some bacteria use a “contractile injection system” to get proteins inside their targets. These are nano-sized little syringes that load up a protein inside of them and then literally inject it into the target. See the image at the top and it’ll make sense. Plus they look like moon landers.

This week’s scientists figured out how to hijack the contractile injection system and turn it into a versatile tool for delivering protein drugs.

Why did they do this, you wonder?

Because we’ve made a lot of protein drugs that don’t work well.

And a big reason they don’t work well? They’re delivered badly.

Delivery systems help address a few big problems with protein drugs:

Proteins…

1. Quickly degrade when they’re injected alone (think IV injections).

2. Don’t enter cells well.

3. Don’t target specific cell types.

So, we need new delivery systems. Bacteria have been delivering protein drugs to mammalian cells for a lot longer than we have and they’re frankly better at it than we are.

If you can’t beat ‘em, join ‘em.

The authors instructed bacteria to produce empty syringes and figured out how to purify them. Next, they used another recent finding to load proteins of their choice into the syringes.

Proteins are highly structured. They fold in specific ways and form defined shapes. However, when proteins are disordered in a specific location, it tells the bacteria syringe to load them as cargo. No one is quite sure why, but it works.

Designing proteins with an extra disordered region makes the syringe see the proteins as cargo and load them for delivery. These disordered “packaging domains” can be used to load any cargo of interest including Cas9, a protein commonly used in gene editing.

Side note: the discovery of CRISPR/Cas9 earned Professors Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize in Chemistry. Only 8 women have been given the award, including 4 since 2018.

The bacteria syringe used in this study originally targeted insects. However, as you might have guessed, insects ≠ humans.

The authors had to figure out what makes the syringes target specific cells to make them target human cells. To do this, they turned to a combination of previous research work and Google’s artificial intelligence protein structure predictor, AlphaFold.

Using these tools, they found that specific proteins on the tails of the syringes were responsible for targeting. Parts of these tail fiber proteins could be switched out with other sequences that enable the targeting of specific markers on human cells.

As a demonstration of the usefulness of the bacterial syringe system, the authors modified their syringes to target human adenocarcinoma cancer cells and loaded them with toxins. This cancer-targeting and toxin-loading led to the syringes killing nearly all of the adenocarcinoma cancer.

They performed a similar study using human leukemia cells and got similar results. The repurposed bacterial syringes were able to target and kill leukemia cells without killing other non-leukemia immune cells.

This shows that the syringe system is highly specific to whatever cell type the tail fibers are targeting. This is important for limiting off-target side effects if this system were to ever be used as a therapy. There wouldn’t be much point in using it as a cancer treatment if it killed off all of your healthy cells in addition to the cancerous ones.

To show the versatility of the system, two gene editing proteins (Cas9 and ZFDs) were delivered and resulted in effective editing.

Together, the cancer and gene editing examples show the system is versatile, specific, and efficient. These features make the bacterial syringe a promising new type of delivery system for treating cancers and genetic diseases such as sickle cell anemia.

Some of the most powerful drugs we have come straight from nature. We might as well deliver them with bio-inspired technology too.

Next week we’ll dive back into the materials world and look at how microplastics can be recycled into battery parts. See you then!

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