Disease-responsive nanoparticles enable ghrelin mRNA therapy in osteoarthritis

Nitin Joshi, PhD, and Jingjing Gao, PhD, of the Department of Anesthesiology at Mass General Brigham, are the co-senior authors of a paper published in Nature Nanotechnology, "A disease-severity-responsive nanoparticle enables potent ghrelin mRNA therapy in osteoarthritis." Mahima Dewani, PhD, is the lead author of this study.

Q: How would you summarize your study for a lay audience?

Osteoarthritis is a highly prevalent joint disease that leads to cartilage breakdown, pain and disability, yet there are still no FDA-approved treatments that can slow or reverse its progression. RNA-based therapies hold great promise because they can silence the molecular signals that drive cartilage degeneration. However, for these treatments to work, they must reach the damaged regions, called lesions, within the cartilage.

Our study developed a nanoparticle platform that enables precise delivery of disease-modifying gene therapies, such as mRNA, directly to lesions after injection into the joint. These nanoparticles are engineered to home in on areas where cartilage has degenerated in osteoarthritis, ensuring that treatment concentrates exactly where it is needed. These nanoparticles can also adapt their targeting based on how severe the disease is, which is important because cartilage damage differs from person to person and changes over time.

Q: What knowledge gap does your study help to fill?

Existing delivery approaches cannot sense where cartilage is damaged and often miss the areas that need treatment most. Our study addresses this gap by developing a delivery system that naturally homes in on damaged cartilage using biochemical signals that arise as osteoarthritis progresses and adapts its targeting as disease severity changes, enabling lesion-specific, disease-responsive gene therapy.

Q: What methods or approach did you use?

Healthy cartilage contains glycosaminoglycans, molecules that give it a strong negative charge. As cartilage breaks down, it loses these molecules and its negative charge decreases. We leveraged this natural shift to design Matrix-Inverse Targeting, or "MINT," nanoparticles, a delivery system designed to do the opposite of conventional targeting. Instead of sticking to a specific molecule, MINT particles are repelled by healthy cartilage rich in glycosaminoglycans and are naturally drawn into damaged areas where these molecules are lost.

Since glycosaminoglycan loss increases with disease severity, more severe lesions attract more nanoparticles. Using this "precision-entry" approach, we delivered an mRNA that instructs cartilage cells to produce ghrelin, a protective protein that is reduced in osteoarthritis.

In collaboration with Dr. Li Zeng from Tufts University, we evaluated the therapeutic effects of these particles in established preclinical models of osteoarthritis to determine whether this approach could reduce cartilage damage and improve pain-related behavior.

Q: What did you find?

We found that our nanoparticles selectively entered and accumulated in cartilage areas where glycosaminoglycans were lost, precisely the regions that worsen as osteoarthritis progresses. Importantly, the more severe the cartilage damage, the stronger the targeting effect. When loaded with ghrelin mRNA, the nanoparticles reduced cartilage breakdown, limited abnormal thickening of the underlying bone, lowered inflammatory signals and decreased activation of pain-related nerve pathways in mouse models.

Q: What are the implications?

This work demonstrates a radically simple way to deliver RNA therapies directly to the specific cartilage lesions that drive osteoarthritis, and to automatically adjust delivery based on how severe the damage is. Because the targeting relies on natural biochemical changes in the tissue, it avoids the need for complex or expensive engineering and is well aligned with current clinical practices for joint injections.

While we used ghrelin mRNA in this study, the platform could support the delivery of other RNA-based treatments, creating a platform strategy for slowing or even reversing cartilage loss. More broadly, this approach provides a blueprint for "disease-responsive" delivery systems that adapt to tissue health in real time, which could transform how we treat other conditions as well.

Q: What are the next steps?

Our next steps are to extend how long the treatment's effects last in the joint and to demonstrate that this platform can deliver a range of clinically relevant RNA therapies. We also plan to test the approach in larger preclinical models that better mimic human knee joints. These studies will help determine how close this technology is to advancing toward future clinical translation.