Engineered Phages Deliver Therapeutic Proteins to Intestines

The human gut is home to hundreds of microbial species, each playing a unique role in maintaining health. Now, one of these microbes might take on an entirely new function: acting as a microscopic internal pharmacist.

A recent study published in Nature Biotechnology highlights how gut bacteria can be engineered to produce and release proteins directly within the lower gastrointestinal tract. This breakthrough addresses a key challenge in drug delivery—ensuring medications reach this part of the body effectively.

While oral medication remains the most common and convenient method of drug administration, the stomach’s natural defense mechanisms often prevent certain substances from passing through. While these mechanisms are essential for blocking harmful pathogens, they can also deactivate gut-targeted therapies before they take effect.

Biologist Bryan Hsu and his research team have developed an innovative solution. They have modified bacteriophages—viruses that specifically infect bacteria—to reprogram bacterial cells, enabling them to generate and continuously release therapeutic proteins.

Harnessing the Power of Bacteriophages

Bacteriophages, or phages, are viruses that exclusively target bacteria. Though less understood than bacteria themselves, their ability to hijack bacterial machinery is well documented. When a phage infects a bacterial cell, it injects its genetic material, turning the cell into a factory that produces more phages. Eventually, the bacterial cell bursts in a process called lysis, releasing a new wave of phages.

This natural cycle inspired Hsu’s team to explore phages as a potential vehicle for drug delivery. Doctoral student Zachary Baker engineered specialized phages that not only replicate but also introduce additional genetic instructions, prompting bacterial cells to produce therapeutic proteins.

Engineered Phages Show Promise in Mice

To test their approach, Baker and Research Assistant Professor Yao Zhang used these engineered phages to treat disease symptoms in mice. Their findings demonstrated promising results:

• Reduced inflammation: The engineered phages released a protein that inhibited an enzyme associated with inflammatory bowel disease.

• Decreased obesity: Another protein promoted satiety in mice on a high-fat diet, mimicking the effects of interventions used to combat obesity in Western diets.

These results offer proof-of-concept for a novel drug-delivery method. Hsu’s team is now exploring the commercial viability of this approach through the National Science Foundation I-Corps program and the Fralin Commercialization Fellowship.

The Next Challenge: Systemic Drug Absorption

While this method successfully delivers therapeutic proteins to the gut, the next hurdle is ensuring these treatments can enter systemic circulation. Hsu likens this challenge to a package delivery system:

“It’s like we’re Amazon. We got the stuff there, we dropped it off on the doorstep. Now we need to figure out how to ring the doorbell.”

As research continues, engineered phages could pave the way for more effective and targeted treatments for chronic diseases. The potential applications extend beyond gut health, opening new possibilities in precision medicine.