Lei Ye, M.D., Ph.D., associate professor in the Department of Biomedical Engineering, and his lab team have published groundbreaking research that proves specially designed nanovesicles—tiny particles made from human stem cells—can help restore blood flow and repair blood vessels in animal models with blocked circulation in their limbs.
Ye worked with first author, Yuhua Wei, postdoc in the Department of Biomedical Engineering, as well as several other faculty (such as Jianyi “Jay” Zhang, M.D., Ph.D.) in the department, to publish “Human induced pluripotent stem cell-derived nanovesicles for the treatment of ischemic limb disease” in Acta Biomaterialia.
The study suggests a scalable, allogeneic approach to treating critical limb ischemia with minimal immune rejection.
The challenge of critical limb ischemia
Critical limb ischemia (CLI) is a form of peripheral artery disease, where blood flow to the lower extremities is critically compromised. “Actually, it’s a quite severe condition,” says Ye, “especially in patients with diabetes.”
Patients experiencing CLI suffer from chronic pain, ulceration, and tissue necrosis. Ultimately, many require limb amputation. Existing treatments (such as angioplasty, bypass surgeries, or cell therapy) are often limited by patient fitness, graft complications, or poor cell survival.
Over the past decade, extracellular vesicles—small, cell-secreted membrane vesicles carrying proteins, RNAs, lipids—have emerged as a non-cellular therapeutic modality. For instance, extracellular vesicles from stem cells can promote new blood vessels from existing ones, a term called angiogenesis. This helps protect vascular cells under ischemia. However, obtaining sufficient yields from live cell cultures has contributed to setbacks when translating from the bench to the bedside.
Moreover, the body may not always react well to live stem cell cultures. Ye and his team looked at how to reduce the vesicles’ immunogenicity for off-the-shelf use. Lower immunogenicity means the immune system would be less likely to attack it as a foreign invader.
Nanovesicles offer breakthrough in safe, scalable production
To create a hypo-immunogenic solution, using CRISPR/Cas9 (a powerful gene-editing tool that allows scientists to make very precise changes to DNA), the team deleted the β2-microglobulin (B2M) gene, which is necessary for HLA class I expression, making the resulting nanovesicles less visible to immune attack.
Instead of waiting for cells to naturally release extracellular vesicles, Ye and team broke down the stem cells in a controlled way to create nanovesicles. This method produced a large yield, over 9,500 NVs from a single stem cell, which is far more than traditional methods.
The nanovesicles measured about 116 nanometers in diameter, had the expected double-layered membrane structure, and carried a stable negative surface charge that helps them remain suspended.
In lab tests, these nanovesicles protected blood vessel cells from damage caused by low oxygen, helped the cells grow and multiply, and did not show harmful effects. All of this suggests they are both effective and safe for further study.
“The nanovesicles are well tolerated by these animal models and also can survive in the ischemic limb to promote perfusion, especially endothelial cells proliferation, which was a significant contribution to rebuild perfusion in the models,” said Ye.
In mouse models with blocked blood flow, treatment with the engineered nanovesicles led to stronger blood flow recovery compared to untreated models. It also showed more new blood vessel growth, illustrated by a higher number of small vessels and more active endothelial cells (the cells that line blood vessels). And finally, there were significant safety levels, with no signs of damage to organs like the liver or kidneys.
Notably, all of these benefits happened without the need for drugs to suppress the immune system, highlighting how the low-immunogenic design of the nanovesicles makes them especially promising for therapy.
The future of vesicle medicine
Now that Ye’s team has shown strong results in early studies, the focus is shifting from bench to bedside.
A patent application is underway to protect the unique method used to create these nanovesicles and their low-immunogenic design. This step not only secures the intellectual property but also helps pave the way for commercial development and partnerships that could bring the therapy to market.
Moving forward, the team’s work signals the start of a new approach—one that Ye’s group calls “vesicle medicine.” Instead of transplanting live cells, which can be unpredictable and risky, the therapy delivers the beneficial signals those cells produce—packaged in stable, safe nanovesicles. If the platform continues to succeed, it could be applied beyond limb disease to other conditions such as heart attacks, strokes, or muscle injuries.
“There is quite a severe disease burden in Alabama, and a lot of the patients, because of obesity or diabetes, have quite a high rate of this kind of ischemic limb disease. I think it's a good opportunity to explore the potential of this therapeutic option within UAB and within Alabama,” said Ye.
While there is still a long road ahead, this patent-pending discovery represents a major step toward turning a laboratory innovation into a therapy that could change lives.