Imma Perfetto
Cosmos science journalist
What if we could hijack a communications system in the body to encourage damaged cells, like those in the hearts of people with cardiovascular disease, to repair themselves?
Researchers at the Baker Heart and Diabetes Institute in Australia are working towards just this. They study extracellular vesicles (EVs), which could overhaul how we deliver therapeutics and monitor and diagnose disease.
EVs are between 30 nanometre- to 1 micrometre-sized lipid sacks which are released from cells to transmit complex information. These EVs interact with other cells in the nearby environment or enter the circulation to reach targets at distant sites in the body, to tell them what to do.
“These little vesicles have basically emerged as a completely new signalling mechanism in the last 10-15 years,” Professor David Greening, head of the Molecular Proteomics laboratory, told Cosmos.
In a recent review, Greening and collaborators described this as the “Cambrian explosion for the EV field.”
“All cells talk, the environment around a cell defines very much what a cell is and what it does,” he says.
“We’re just trying to understand how that happens and, when things don’t go right, how we can interfere with that.”
EVs deliver their messages via 2 broad mechanisms.
An EV can precisely interact, through receptors on its surface, with the outside of a target cell to induce changes within it. It can also protect and shuttle therapeutic agents – such as proteins, nucleic acids, viruses, and compounds – and deliver them directly into a cell.
Through these mechanisms, EVs induce functional and biological responses to regulate various processes in the body. In the heart, they have been shown to play important roles in maintaining homeostasis, and in the pathogenesis of heart diseases.
“A skin cell or a blood vessel cell will release vesicles that do many things differently, to say, a cancer cell or an injured heart cell,” says Greening.
The goal is to redesign EVs with repair and regenerative functions to very potently and precisely alter or improve cells.
Greening’s main area of interest lies in the heart and cardiovascular disease (CVD) – the leading cause of death globally.
The heart has limited ability to repair and regenerate itself, so the goal is to modify EVs from stem cells and deliver them to heart cells to reprogram them from a disease or pre-disease state to a healthy one.
“We can put cargo in that protects certain cells,” he explains.
“We can change the surface of those vesicles to make them stick [to specific cells] or to hide them from circulation, so that certain immune cells don’t take them up … basically enhance their tool as a therapeutic.
“They’re very amenable to and very versatile to be modified.”
Greening’s team is also exploring how to eventually deliver these new therapeutics, including designing patches made of biomaterials which could be placed directly on the heart to release EVs safely over time.
But the promise of EVs doesn’t end there. They are naturally present and stable in various biological fluids, including blood, and their internal cargo and external surface “barcode” is specific to the injured, altered, or non-healthy cell type which released them.
In other words, they could be used as diagnostic and monitoring tools.
“You can imagine, as a diagnostic tool, this offers a huge advantage to sample over time the progression or onset of disease, or a treatment response, or even how you age, or any changes within your body,” says Greening.
In 2024 the FDA granted “Breakthrough Device Designation” to EvoLiver, a test for detecting EVs associated with hepatocellular carcinoma (HCC), the most common form of primary liver cancer.
However, there are still major challenges to overcome before EV therapeutics can be fully realised. Greening says one challenge is scalability; another is regulatory approvals.
“There’s about 500 clinical trials that are occurring as we speak, and most of them are focusing on safety,” he says.
“Probably the biggest challenge the entire field faces right now is that vesicles … are really diverse in their size, in where they’re from, in what they do and, importantly, how they do it.
“You have this signalling tool that does everything and more, how do you know precisely what it does, and how it does it?”
“How does an entire organ change with a vesicle, or how do all these vesicles signal? You need these holistic quantitative tools to do this.”
Greening’s team is tackling the challenge using mass spectrometry-based proteomics to gain insights into the proteins within the heart, where in the cell they’re expressed, and to what extent.
“The number of people that don’t survive [heart attack events] because of a lack of targeted therapies is [why] we need these tools,” he says.
“If we have all these tools … that can help the body heal and protect itself … then isn’t that sort of the goal? I think that’s where our vision is.
“So, who knows? Maybe come back and speak to us in 5 years.”
