Researchers Develop “Disease-Responsive” MINT Nanoparticles to Deliver mRNA for Osteoarthritis Treatment

January 14 2026-Osteoarthritis (OA) is a highly prevalent degenerative joint disease characterized by progressive cartilage breakdown, chronic pain, and disability, yet there are currently no FDA-approved therapies that can slow or reverse disease progression. RNA-based therapies offer a promising disease-modifying approach by silencing molecular drivers of cartilage degeneration, but effective treatment requires precise delivery to damaged cartilage lesions within the joint.

In a study titled “A disease-severity-responsive nanoparticle enables potent ghrelin mRNA therapy in osteoarthritis,” published in Nature Nanotechnology, researchers report the development of a novel nanoparticle delivery platform that enables lesion-specific, disease-responsive delivery of gene therapies such as mRNA following intra-articular injection.

The nanoparticles are engineered to selectively accumulate in regions of cartilage degeneration, ensuring therapeutic payloads concentrate where disease activity is highest. Importantly, the system adapts its targeting based on disease severity, addressing the heterogeneity and dynamic progression of osteoarthritis across patients.

Filling a critical delivery gap

Conventional intra-articular delivery approaches lack the ability to distinguish healthy from damaged cartilage, often resulting in suboptimal exposure of diseased regions. This study addresses that limitation by exploiting a fundamental biochemical change in osteoarthritis progression: the loss of glycosaminoglycans (GAGs), which normally confer a strong negative charge to healthy cartilage.

As cartilage degrades, GAG content and negative charge decrease. The researchers leveraged this shift to design Matrix-Inverse Targeting (MINT) nanoparticles, which are repelled by healthy, GAG-rich cartilage but preferentially enter areas where GAGs are depleted. Because GAG loss increases with disease severity, more advanced lesions naturally attract higher nanoparticle accumulation.

Using this precision-entry strategy, the team delivered mRNA encoding ghrelin, a protective protein known to be reduced in osteoarthritic cartilage. The therapeutic effects were evaluated in established preclinical models of osteoarthritis, in collaboration with Dr. Li Zeng of Tufts University.

Key findings

The study demonstrated that MINT nanoparticles selectively accumulated in cartilage lesions with GAG loss, with targeting strength proportional to disease severity. When loaded with ghrelin mRNA, the nanoparticles significantly reduced cartilage degeneration, limited pathological subchondral bone thickening, suppressed inflammatory signaling, and decreased activation of pain-related neural pathways in mouse models of osteoarthritis.

Broader implications

This work introduces a simple yet powerful paradigm for lesion-specific RNA delivery in osteoarthritis, using endogenous biochemical cues rather than complex targeting ligands. The approach aligns well with standard clinical joint injection procedures and avoids the need for expensive or highly engineered targeting strategies.

Although ghrelin mRNA was used as a proof of concept, the platform is broadly applicable to other RNA-based therapeutics, positioning MINT nanoparticles as a potential platform technology for disease-modifying osteoarthritis treatments. More broadly, the study provides a blueprint for disease-responsive delivery systems that dynamically adapt to tissue health in real time.

Next steps

Future work will focus on extending the durability of therapeutic effects within the joint, evaluating delivery of additional clinically relevant RNA payloads, and testing the platform in larger preclinical models that more closely resemble human knee joints. These studies will help define the translational path toward clinical development.

The study was led by Mahima Dewani, Ph.D., with Nitin Joshi, Ph.D., and Jingjing Gao, Ph.D., of the Department of Anesthesiology at Mass General Brigham serving as co-senior authors.