Osteoarthritis affects over 500 million people worldwide—and those numbers are expected to double by 2050—and still there is no medicine that specifically treats the disease itself.

One reason is that osteoarthritis is highly complex. To start with, it affects more than one tissue: it primarily damages cartilage, but also bone and the synovium (the soft tissue lining the joint). To make things even harder, the disease’s development involves multiple biological processes, including inflammation, programmed cell death (apoptosis), and tissue breakdown (catabolism).

Additionally, osteoarthritis is commonly detected once symptoms are evident, by which point the tissue is already severely damaged and difficult to restore.

Treatments used today for osteoarthritis patients mainly focus on relieving symptoms such as pain and stiffness rather than slowing or stopping disease progression. What is urgently needed is a therapy that can change how the disease develops and stop increasing damage, what health professionals call a “disease-modifying drug.”

Disease-modifying candidates for osteoarthritis

The drug candidate closest to the clinic is loracivivint, which is now being evaluated by the US Food and Drug Administration. The drug works by modulating gene expression and inhibiting two proteins linked to inflammation: CLK and DYRK kinases. While it has shown some improvement in pain in osteoarthritis patients treated in clinical trials, the results have been modest, and it remains unclear whether it will be approved for clinical use.

Many scientists around the world are exploring new approaches to develop a disease-modifying osteoarthritis drug. One example is a study recently published in Small, where a team at the at the Sichuan University in China present a nanoplatform to deliver microRNA molecules directly to affected joints. The results show therapeutic efficacy in animal models, offering a promising strategy for a future osteoarthritis therapy in humans.

Engineering a microRNA delivery system: A DNA-RNA Lego building

The team involved in the study chose a microRNA that had previously been shown to have potent anti-inflammatory and cartilage-protective activities: miR-143-3p. However, translating microRNA-based therapies into the joint is limited by delivery challenges, as these molecules degrade rapidly in biological fluids.

To overcome this, the group designed a particular DNA carrier: a 3D nanostructure in tetrahedral shape with four triangular faces, six edges (made of short DNA sequences), and four vertices. Then, like a Lego-building approach, they incorporated three miR-143 molecules in the vertices that extended along three edges to form one face of the tetrahedron; they called it a “vertex-integrated tetrahedral DNA nanoframe miR-143 system,” or “Tvi-miR143” for short.

DNA tetrahedra with microRNA incorporated into three vertices, for delivery into joints affected by osteoarthritis. Adapted with permission from 10.1002/smll.202511570.

“Too many osteoarthritis RNA papers nominate a target and ignore the brutal translational problem of getting nucleic acids into the joint, into the right cells, with enough stability and acceptable repeat dosing,” says Edward Ahn, chief executive officer at MEDIPOST Inc., a biotech company developing therapies to treat inflammation-driven degenerative diseases such as osteoarthritis, who was not involved in the study. “[Tvi-miR143] is a real engineering improvement over simpler ‘cargo attached to scaffold’ approaches.”

Testing its stability for clinical use

The scientists studied the nanostructure’s stability under different conditions, simulating in the lab the conditions it encounters when injected into the body. They found that in a medium rich in proteins and other biological particles (fetal bovine serum), where free miRNA typically degrades within minutes, Tvi-miR143 retained 40 % of its miRNA after 24 hours of exposure, highlighting the markedly enhanced stability by being attached to the DNA nanoframe.

Considering future clinical use, the team evaluated the storage stability of Tvi-miR143. They found that, at 25 degrees Celsius (ambient conditions), the structure retained more than 75 % miRNA activity after one week, potentially eliminating the need for cold chain storage and reducing costs and logistical complexity.

Putting the nanostructure into action

The team then assessed the intra-articular retention of Tvi-miR143 in vivo by labeling either the nanostructures or the free microRNA with a fluorescent marker and tracking the signal over time in rat knees.

Compared with miR-143 alone, Tvi-miR143 produced a stronger fluorescent signal at 120 minutes post-injection, indicating improved retention within the joint. Notably, Tvi-miR143 fluorescence was higher in injured joints from post-traumatic osteoarthritis rats than in healthy joints, suggesting enhanced accumulation in diseased tissue. “For an intra-articular therapy, retention matters,” says Ahn. “Showing prolonged joint fluorescence is useful.”

To assess the nanostructure functionality, the team performed histological analysis of the injected joint tissue and compared the effects of Tvi-miR143, free miR143, the DNA tetrahedron alone, and dexamethasone (a potent anti-inflammatory corticosteroid). After 2 months of treatment following three intra-articular injections per week, Tvi-miR143 showed the strongest protective effect on cartilage.

Compared with the other treatments, it better preserved cartilage structure (as evidenced by an even joint surface), reduced signs of tissue breakdown (the Tvi-miR143 condition showed less extracellular matrix breakdown), and promoted cartilage repair (as indicated by greater cartilage thickening than in other conditions). 

“[The results] demonstrate a credible disease-modifying preclinical signal,” says Ahn.

However, the study does not address an outcome that is particularly important for patients with osteoarthritis: pain relief. As Ahn explains, improvements in cartilage structure do not necessarily translate into reduced pain, since human osteoarthritis pain does not always correlate with the degree of cartilage damage. He adds that “without a sustained behavioral analgesic endpoint in the efficacy package, any statement on pain remains mechanistically plausible but unproven.”

Future studies will need to determine whether Tvi-miR143 can relieve pain, first in animal models and eventually in humans. The authors also note another limitation: the work was conducted in a post-traumatic osteoarthritis model, whereas most human osteoarthritis cases are heterogeneous in origin and progression. Taken together, these limitations highlight the need for further validation before clinical translation. “It is not yet evidence of clinical efficacy,” says Ahn, “but [Tvi-miR143] is a credible step toward an intra-articular nucleic acid therapy for [osteoarthritis].”

Reference: X. Chen et al., Vertex-Integrated Tetrahedral DNA Nanoframe Enhances miR-143-3p Delivery for Osteoarthritis Therapy, Small (2026). DOI: 10.1002/smll.202511570

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