Drug discovery and novel disease treatments are major areas of research, with constant innovation. Delivering these drugs and treatments completely and precisely has been a major hurdle that researchers continue to grapple with.
Now, a research team at the Ottawa Hospital, led by Michael Rudnicki, PhD, director of the regenerative medicine program, has identified an 18-amino-acid sequence that enables proteins to hitch a ride on exosomes to transport contents around the body to specific targets. Their work titled, “Identification of the Wnt signal peptide that directs secretion on extracellular vesicles,” was published in Science Advances.
Exosomes, small vesicles that leave the cell with a variety of contents and intended locations, like lipid nanoparticles (LNPs), are the focus of much research into effective drug delivery and cell therapy systems. Their potential for drug delivery has spurred significant interest in academia and industry with a recent report from DelveInsight predicting “tremendous” growth in the field.
While LNPs are customizable due to their synthetic nature, exosomes may be more biocompatible as they are naturally occurring. However, harnessing exosomes as an effective and precise drug delivery method has been a challenge.
Rudnicki said, “Proteins are the body’s own homemade drugs, but they don’t necessarily travel well around the body.” Combining innately produced materials with materials that can move in a directed fashion to specific targets within the body is a primary goal for drug delivery research.
The new study focused on Wnt7a, a protein essential for development, growth, regeneration, and cancer. “Researchers have been trying for years to turn Wnt7a into a muscle regeneration drug, but it is very difficult to deliver Wnt7a throughout the body, since it is covered in fatty molecules that don’t mix well with body fluid,” said first author Uxia Gurriaran-Rodriguez, PhD, Center for Cooperative Research in Biosciences (CIC bioGUNE).
Wnt7a was identified as a long-distance signaling molecule found on the surface of exosomes following muscle injury. Due to its many hydrophobic components, it was necessary to isolate smaller portions of the Wnt7a protein to determine the smallest functional segment required for attachment to an exosome. Through selective deletion of various components of Wnt7a, the team found the smallest functional segment needed for exosome binding.
This segment turned out to be an 18-amino-acid sequence, which the team termed Exosome Binding Peptide (EBP). The team found that “addition of EBP to an unrelated protein directed secretion on extracellular vesicles.” EBP binds to coatomer proteins, proteins that coat membrane-bound transport vesicles, on exosomes, and through follow-up structural experiments, the team determined this is a conserved function across the Wnt protein family. EBP can be used to direct other proteins to exosomes, effectively allowing for targeted delivery of exosomes and their contents.
“Now that we know how Wnt7a attaches to exosomes, we have solved this problem and can now accelerate the development of drugs for devastating diseases such as Duchenne muscular dystrophy,” said Gurriaran-Rodriguez.
The authors of the study emphasize the transformative potential of their findings. “This discovery allows us to harness exosomes to deliver any protein throughout the body,” said Rudnicki. “It opens the door to a whole new field of drug development.” By enabling proteins to leverage the natural transport system of exosomes, the research opens new avenues for systemic protein delivery and innovative therapeutic strategies.