Rethinking Osteoarthritis With Extracellular Vesicles

Osteoarthritis remains one of the most prevalent and debilitating joint diseases, with current treatments primarily focused on symptom management rather than disease modification. While corticosteroid and hyaluronic acid injections provide temporary relief, they do not address the underlying mechanisms driving cartilage degradation and inflammation. 

Extracellular vesicles (EVs) derived from mesenchymal stromal cells have emerged as a promising avenue in regenerative medicine, offering potential anti-inflammatory and regenerative effects without the challenges associated with whole-cell therapies. In a recent study published in the Journal of Nanobiotechnology, Francisca Alcayaga-Miranda and Maroun Khoury, along with their colleagues at the Universidad de los Andes in Santiago, evaluated the use of umbilical cord-derived EVs for knee osteoarthritis. Their findings suggest that EV therapy could influence macrophage polarization, reduce cartilage degradation, and offer sustained clinical benefits. 

Here, Alcayaga-Miranda and Khoury tell us more about their research and the next steps toward clinical translation.

What were the most surprising findings from your study?
 

One of the most striking findings of the study was the ability of UC-MSC-derived EVs to shift macrophages towards an M2b anti-inflammatory phenotype, highlighting their role in modulating inflammation and promoting cartilage repair. Preclinical models also demonstrated that EVs helped preserve articular cartilage and reduced its degradation, an effect that had not been extensively documented in previous research.

Another key observation was that EVs remained confined to the joint for at least 72 hours after intra-articular administration, as confirmed by biodistribution studies. This retention suggests a favorable safety profile because it limits systemic distribution and reduces the risk of off-target effects.

In the first-in-human study, a single intra-articular injection led to sustained clinical improvement for more than a year, with no reported adverse events, reinforcing the potential of EVs as a safe and long-lasting therapeutic option for osteoarthritis.

No serious adverse events were reported. The only observed side effect was mild and transient post-injection pain, which was easily managed with standard analgesics. There were no signs of synovitis, joint effusion, or systemic immune responses during the 12-month follow-up, further supporting the excellent safety profile of EVs therapy.

How does this therapy compare to existing osteoarthritis treatments?
 

Unlike corticosteroids and hyaluronic acid (HA), which primarily focus on symptom relief, EVs therapy has the potential to modify disease progression. Corticosteroids may provide rapid pain relief, but their effect is temporary, and prolonged use can accelerate cartilage deterioration. HA, on the other hand, improves joint lubrication but has limited effects on chronic inflammation or cartilage repair. In contrast, EVs reduce inflammation while also fostering a pro-regenerative environment in the joint, offering a potentially longer-lasting, disease-modifying benefit. This must be confirmed with further studies, of course. 

What are the next challenges for this work?
 

Several challenges remain, including a standardization of production to ensure that each batch of EVs maintains the same composition and biological activity crucial for regulatory approval. More data for regulatory approval is another challenge. As of now, no EVs-based therapy has been approved for osteoarthritis, requiring the establishment of clear potency tests, QC parameters, and mechanisms of action.

Further challenges include commercial scalability and the development of efficient strategies to produce EVs in clinically relevant volumes without compromising quality, and validation in larger clinical trials.

How did you ensure batch-to-batch consistency in the clinical-grade EVs production process?
 

We converted lab protocols to standard operating procedures. A GMP-compliant manufacturing protocol was established to ensure consistency, including carefully characterized parental cells (UC-MSCs) with well-defined surface markers; rigorous quality control measures, including nanoparticle tracking analysis for size and concentration, flow cytometry for EVs markers, and proteomic/miRNA profiling; and stability assessments, confirming that EVs retained their biological activity after 24 months of storage at –80 °C. These remained stable for up to 24 hours post-thawing at 2-8 °C.

How do EVs influence macrophage polarization and their role in cartilage regeneration?
 

EVs exert an immunomodulatory effect by shifting macrophages from a pro-inflammatory (M1) state to an anti-inflammatory (M2b) phenotype, which plays a key role in inflammation resolution and tissue repair. This effect is driven by STAT1 inhibition, that is reducing the activation of inflammatory pathways; upregulation of miRNAs such as miR-222, miR-27a, and miR-125a-5p, which promote M2b macrophage differentiation; increased secretion of IL-10 and VEGF, enhancing tissue remodeling and immune modulation; and protection of chondrocytes from oxidative stress, reducing apoptosis and cartilage degradation.

What are the next steps for this research? Are you planning further trials?
 

Absolutely! A registered phase I clinical trial (NCT 06431152) is currently underway, designed as a dose-escalation study in patients with moderate knee osteoarthritis. The primary objective is to evaluate safety and feasibility, which will help determine the optimal dose for larger phase Ib and II trials focused on efficacy and durability.

Could EVs-based therapies potentially be applied to other joint diseases or inflammatory conditions?
 

Because of their anti-inflammatory and regenerative properties, EVs could be explored for other degenerative joint diseases, including rheumatoid arthritis and hip/shoulder osteoarthritis; systemic inflammatory conditions, such as autoimmune diseases (e.g. lupus); and post-traumatic joint injuries, where EVs could accelerate healing and prevent long-term damage.

EVs-based therapies have the potential to redefine regenerative medicine by providing easier logistics, especially with lyophilization, enabling engineered EVs for targeted drug delivery. I also foresee an expansion into personalized medicine and applications beyond osteoarthritis and into cardiovascular, neurodegenerative, and metabolic disorders.