Researchers from Mass General Brigham have developed a new nanoparticle platform designed to deliver gene therapies directly to damaged cartilage in osteoarthritis. The study, published in Nature Nanotechnology, was led by co-senior authors Nitin Joshi, PhD, and Jingjing Gao, PhD, with Mahima Dewani, PhD, as the lead author.
Osteoarthritis is a common joint disease that results in cartilage breakdown and pain. Currently, there are no FDA-approved treatments that can slow or reverse its progression. RNA-based therapies have shown potential for treating osteoarthritis by targeting the molecular causes of cartilage degeneration. However, these therapies face challenges in reaching the specific areas within the cartilage that are most affected.
"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," said the research team. "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."
The researchers addressed a key limitation of existing delivery methods: their inability to sense and target damaged regions within cartilage. "Existing delivery approaches cannot sense where cartilage is damaged and often miss the areas that need treatment most," they stated. "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."
The approach relies on differences between healthy and diseased cartilage at the molecular level. Healthy cartilage contains glycosaminoglycans (GAGs), molecules responsible for its strong negative charge. As osteoarthritis progresses and GAGs are lost from damaged regions of cartilage, these areas become less negatively charged.
"We leveraged this natural shift to design Matrix-Inverse Targeting, or 'MINT,' nanoparticles," explained the team. "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."
In collaboration with Dr. Li Zeng from Tufts University, preclinical models were used to test whether this targeted approach could reduce damage and improve pain-related outcomes.
"We found that our nanoparticles selectively entered and accumulated in cartilage areas where glycosaminoglycans were lost," said the researchers. "Importantly, the more severe the cartilage damage, the stronger the targeting effect." When loaded with ghrelin mRNA—a protein reduced in osteoarthritis—the nanoparticles helped reduce further breakdown of tissue and abnormal bone thickening while lowering inflammation markers and pain pathway activation.
The findings suggest broader implications for both osteoarthritis treatment strategies and other diseases requiring targeted drug delivery systems: "This work demonstrates a radically simple way to deliver RNA therapies directly to the specific cartilage lesions that drive osteoarthritis... Because the targeting relies on natural biochemical changes in tissue... it avoids complex or expensive engineering."
Looking ahead at future research directions: "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," they said. Further studies will involve larger animal models more similar to human knee joints before moving toward clinical trials.
