Pursuing Disease-Severity Targeting in Osteoarthritis, With Nitin Joshi, PhD

A novel anionic nanoparticle system that autonomously targets cartilage damage proportional to disease severity — without antibodies or external programming — has demonstrated the ability to deliver ghrelin mRNA to focal osteoarthritis (OA) lesions, producing simultaneous reductions in cartilage degeneration, subchondral bone thickening, and pain in preclinical models, according to research published in Nature Nanotechnology.

To discuss the findings, RheumatologyLive spoke with Nitin Joshi, PhD, Assistant Professor at Harvard Medical School and Associate Bioengineer in the Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women's Hospital in Boston, co-senior author of the study. Osteoarthritis affects hundreds of millions of people worldwide yet has no United States Food and Drug Administration (FDA)-approved treatment capable of slowing or reversing its structural progression — a gap that has persisted largely because existing intra-articular therapies distribute non-specifically across the cartilage surface rather than concentrating where degeneration is most severe. Prior attempts at targeted delivery have relied on antibody-coated nanoparticles that bind overexpressed surface receptors, an approach Joshi described as mechanistically sound in principle but practically limited: antibody conjugation complicates manufacturing, and the strategy frequently fails to translate from rodent models to human tissue due to differences in receptor affinity and protein absorption from synovial fluid that can mask targeting ability.

The platform developed by Joshi and colleagues sidesteps these limitations entirely through what the team terms matrix inverse targeting (MINT) — an antibody-free strategy that exploits the progressive depletion of glycosaminoglycans (GAGs) from cartilage as OA worsens. Healthy cartilage is densely negatively charged due to its high GAG content, which electrostatically repels the anionic MINT nanoparticles. As GAGs are lost in degenerating regions, that repulsion diminishes and nanoparticle accumulation increases proportionally — meaning the more severe the lesion, the stronger the targeting effect, automatically and without any dose adjustment required. All materials used are biocompatible and available in off-the-shelf quantities, making the platform considerably more scalable than antibody-based alternatives.

Loaded with ghrelin mRNA — chosen for its established chondroprotective properties — the MINT nanoparticles achieved greater than 50% reduction in cartilage degeneration compared to controls with weekly intra-articular injections in a mouse OA model, while also reducing subchondral bone thickening, lowering inflammatory markers, and decreasing activation of pain-related nerve pathways.

Joshi emphasized the multi-tissue impact as a critical practical advantage: patients diagnosed with OA are typically already in advanced stages and actively suffering from pain, making a single disease-modifying injection that simultaneously addresses structural progression and symptom burden far more clinically viable than a purely structural intervention requiring separate analgesic management. Next steps include evaluating durability of therapeutic effects, testing alternative RNA payloads including siRNA to silence pathological pathways, and scaling to larger preclinical models with joint geometry more representative of the human knee.

“Here, the advantage would be that with a single injection of a disease modifying therapeutic you're controlling cartilage degeneration. You're controlling controlling the subchondral bone thickness changes. And you're also controlling pain, which is very, very critical,” Joshi said.

Reference

Dewani M, Mamidwar AR, Rawal M, et al. A disease-severity-responsive nanoparticle enables potent ghrelin messenger RNA therapy in osteoarthritis. Nat Nanotechnol. 2026. doi:10.1038/s41565-025-02101-0.