Using Ghrelin mRNA for the Smart Targeting of Damaged Joints

Osteoarthritis is one of the most common joint disorders in the world—and a particularly insidious one. Affecting more than 500 million people globally according to the World Health Organization, it steals mobility, sleep, and quality of life. Despite its prevalence, current treatments only manage pain and stiffness, leaving the underlying cartilage damage unaddressed. Patients face worsening degeneration, rising costs, and shrinking treatment options as the disease progresses.

“There is no FDA-approved treatment that can slow or stop osteoarthritis,” says Li Zeng, associate professor of immunology at Tufts University School of Medicine. “We can treat pain, but that doesn’t change the biology of the disease. To make progress, we need a new drug and a tunable strategy to cater to people with different disease severity, and to be able to deliver that drug to the places where cartilage is breaking down.”

With funding from the Ellison Foundation—and deep collaboration between Tufts and Mass General Brigham—her lab is advancing targeted approaches at the intersection of biology and nanotechnology.

In a recently published study in Nature Nanotechnology, Zeng and her collaborators highlight a nanoparticle platform designed to deliver a novel therapeutic directly to damaged cartilage. The treatment instructs cells to produce ghrelin, a peptide that the Zeng lab had shown to protect cartilage and reduce degeneration. Once inside the joint, the platform automatically adjusts delivery based on disease severity. Known as matrix-inverse targeting (MINT), it exploits a basic feature of osteoarthritis: as cartilage breaks down, it loses negatively charged molecules, creating openings that allow nanoparticles to “squeeze in” and deliver their cargo exactly where it’s needed.

“That’s what we need: treatments that know where to go,” Zeng says. “If we can reach the damaged regions, we have a real chance of changing the course of the disease.” Zeng is a senior author on the study.

Here, Zeng shares insights about why treatment for osteoarthritis is elusive, the significance of the support she received from the Ellison Foundation for her work, and what needs to happen for research from the lab to translate into clinical results.

Why has osteoarthritis been so difficult to treat, even though it’s so common?

Zeng: Osteoarthritis is extremely heterogeneous, meaning different people have different levels of cartilage loss, different histories of injury or activity, and different mechanical forces acting on the joints. That makes everything harder. One person might have just a few early lesions, while another has widespread deterioration. The variability makes it difficult to measure whether a treatment is working, which is one reason we still don’t have an FDA-approved therapy that slows or stops the disease.

Why ghrelin?

Ghrelin is a hormone in the body. It is a small peptide made of only 28 amino acids. Its level is increased when hungry and decreased after eating—that is why it is called a hunger hormone. We have previously found ghrelin to be beneficial to the joint tissues because it fights inflammation and promotes joint cartilage production. Given that there are no FDA-approved drugs for osteoarthritis, it is all the more important to develop ghrelin as a potential therapeutic. However, to use it in the clinic, it is necessary to identify an effective delivery strategy.

What makes your nanoparticle platform different from previous delivery approaches?

The idea behind MINT is to let the disease itself guide where the therapy goes. I compare cartilage degeneration to a road surface: in early stages, there might be just one or two small “potholes,” while in advanced disease those damaged areas can expand or connect. In healthy cartilage, a strong negative charge keeps nanoparticles out; when the “potholes” form, that charge is reduced and those regions become accessible.

We tune the nanoparticles so they stay out of healthy tissue but enter these damaged sites. The delivery automatically scales with disease severity because the tissue’s condition determines where the particles go. That built-in responsiveness is what sets this approach apart.

Why turn to mRNA instead of delivering a drug or protein directly?

In this study, we use mRNA to produce ghrelin. If you inject the peptide directly, the body clears it quickly and you would need to inject it frequently—daily, in some animal models. That’s not realistic for patients. With mRNA, the cells can make the protein themselves. It’s a way of enabling the tissue to produce what it needs. 

You’ve mentioned the importance of early philanthropic support—what did that make possible?

Early funding from the Ellison Foundation was essential. Before applying for large NIH grants, you need preliminary data that shows the idea has real potential and that the collaboration works. Their support helped us generate early results, demonstrate proof of concept, and make a stronger case for federal funding.

What are the next steps on the path toward clinical translation?

Translation takes time and evidence. We’re working to extend how long the therapy lasts, improve the design of both the mRNA and the nanoparticles, and evaluate the platform in models that better reflect human knees. Ultimately, I want this to benefit many people—that’s in line with both Tufts’ mission and the Ellison Foundation’s. It won’t happen overnight, but I do believe this approach might represent the future of osteoarthritis care.

Citation: Dewani, Mahima., et al. “A disease-severity-responsive nanoparticle enables potent Ghrelin mRNA therapy in osteoarthritis.” Nature Nanotechnology. DOI: https://www.doi.org/10.1038/s41565-025-02101-0