A quiet revolution is underway in modern medicine: Drug development is aiming to move from managing disease to correcting it through RNA and gene-editing therapies. But delivering these treatments safely and precisely to the right cells remains a major hurdle—especially in hard-to-target organs like the brain and kidneys.
Now, researchers led by a University of Ottawa Faculty of Medicine team offer highly compelling evidence that an elegant, nature-inspired solution lies in ultra-tiny, bubble-like structures called small extracellular vesicles (sEVs). These metabolic messengers refined over millions of years of evolution carry RNA – a nucleic acid that is a chemical cousin of DNA – and other molecules between cells.
In a nutshell, the research team's new findings show that not all sEVs are alike: their cell of origin determines where they travel, with certain vesicles naturally targeting specific tissues in the body.
This discovery could unlock powerful new strategies for precise, effective delivery of next-generation therapies piggybacking on these nanometer-scale particles.
Rethinking drug delivery
Dr. Derrick Gibbings , senior author of this innovative studynorth_eastexternal link published in the journal Cell Biomaterials, says the international research team (which included scientists from Brazil and the U.S.) took their cues from biology.
"Our approach was to learn from nature—and work with nature – to find sEVs that could deliver to the tissues and cells where there were the most compelling targets for siRNA therapeutics," he says, referring to a powerful tool to suppress the expression of specific genes. "And to identify targets with large patient populations and high need."
This is important because over the last decade, there's been considerable excitement about small extracellular vesicles and their potential as drug delivery vehicles. But so far, it's hardly been a slam dunk because the overall approach may be faulty. Global companies invested heavily in advancing this technology but struggled to achieve wins because they assumed one type of sEV could work universally across the body.
Dr. Gibbings argues that this approach overlooked a basic principle of biology: communication between cells is highly specific. He says the fact that extracellular vesicle communication is very targeted and controlled "shouldn't be surprising if one thinks of sEVs as a biological communication device."
Instead of trying to force a one-size-fits-all solution, his research team took a different path. The multidisciplinary collaborators explored how sEVs naturally behave and then selected those best suited to reach the specific tissues they were aiming for.
Here's how Dr. Gibbings puts their targeted approach: "sEVs carry specific messages to specific cells. If your house is on fire, you don't phone your cardiac surgeon or your mechanic. If your computer crashes, you don't phone your plumber."
Precision in action: Targeting kidneys and the brain
This common-sense strategy paid off. The team identified sEVs that, when injected into the bloodstream, could deliver siRNA directly to the kidneys, reducing disease symptoms in mouse models of chronic kidney disease.
Importantly, they also found that sEVs could successfully deliver treatments to the brain when directly administered into the central nervous system, improving outcomes in a model of neurodegenerative disease.
The team methodically demonstrated similar success in larger animal models, with results that scaled predictably based on body size and were not substantially altered by species-specific biological differences. This evidence suggests the researchers' approach could potentially translate well to human treatments down the line.
Scaling up for clinical impact
The team's study builds on decades of exciting progress in siRNA therapeutics, which belong to a class of gene-silencing drugs that utilize small interfering RNA molecules. As Dr. Gibbings notes: "siRNAs are incredible therapeutics… A single dose… can block expression of a disease-causing gene for 6 months."
There are various hurdles still to clear. Producing sEVs at large scale and improving how long siRNA treatments last in the body are perhaps the main challenges for the global scientific community. But Dr. Gibbings is optimistic. He and his team are now seeking partners to move the technology into clinical trials, with a particular focus on severe kidney diseases that currently have limited treatment options.
"We have collected a lot of data that shows that sEVs can be effective, safe and scalable delivery vehicles. We are hoping to convince investors or industry partners to work with us to advance these towards clinical trials. Alternatively, I would like to try to find doctors to collaborate with to advance these into clinical trials in academia," says Dr. Gibbings, Professor in the Department of Cellular and Molecular Medicine and uOttawa's Associate Vice-President, Research Support and Infrastructure.
He's particularly bullish on the possibility of using this as a therapeutic for a chronic kidney disease that is caused by a genetic variation in the APOL1 gene. "There are a very large number of patients, and they frequently progress to needing transplants and are also dying of this disease."
Ottawa ecosystem's leadership in fast-moving field
The newly published work led by Dr. Gibbings is among many impactful collaborations focusing on extracellular vesicles in the broad Ottawa research community. To name just a few prominent investigators in this space: Dr. Dylan Burger has become a national and international leader in the growing field, while Drs. John Bell and Carolina Ilkow are using their world-leading expertise to develop EVs for cancer treatments.
Because extracellular vesicles are too small to be visible with most microscopes there are no shortage of challenges in studying them. But Dr. Gibbings describes it as a uniquely exciting field for medical investigators exploring mechanisms of long-distance communication for cells and how to better treat a raft of complex diseases.
"It's kind of like we just discovered that cells use a new media like phones or TikTok for communication and not only face-to-face conversation," he says. "So we're discovering what information and messages they are sharing, and how we can reprogram that to treat disease."
