‘Smart’ solution for osteoarthritis: nanoparticles deliver targeted therapy to repair cartilage damage
An innovative nanoparticle platform adjusts mRNA delivery to osteoarthritic joints based on the severity of cartilage degeneration.
Researchers from Mass General Brigham, Harvard Medical School and Tufts University (All MA, USA) have developed a ‘smart’ nanoparticle carrier for disease-modifying mRNA therapies. These therapeutics can be delivered directly to the site of cartilage degeneration in models of osteoarthritis, a disease that currently does not have an FDA-approved treatment that can slow or reverse it.
Osteoarthritis is a prevalent joint disease that breaks down cartilage. Although RNA therapeutics have shown promise for treating the disease, more targeted delivery approaches are needed to maximize their efficacy. This limitation motivated Mahima Dewani (Harvard Medical School), Nitin Joshi, Jingjing Gao (both Mass General Brigham) and colleagues to develop a novel anionic nanoparticle strategy, called matrix-inverse targeting (MINT) nanoparticles, which can adapt its targeting depending on disease severity.
MINT nanoparticles work by leveraging a natural charge shift that occurs during the breakdown of healthy cartilage. Glycosaminoglycans, molecules abundant in healthy cartilage, have a strong negative charge; as cartilage degenerates, its negative charge decreases. MINT nanoparticles are repelled by glycosaminoglycan-rich tissue’s negative charge, instead gravitating towards cartilage with weaker negative charge.
Largest genetic investigation into osteoarthritis
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The researchers tested their approach by loading a reporter gene, luciferase mRNA, into their MINT nanoparticles and delivering them intra-articularly to mouse models with varying severities of osteoarthritis. Recognizing that the luciferase mRNA displayed disease-severity-responsive expression, they used the same strategy to deliver ghrelin mRNA – which instructs cartilage cells to produce the protective protein ghrelin – to the osteoarthritic mouse models.
They found that this precision approach demonstrated stronger targeting of more damaged cartilage, adapting based on the severity of tissue breakdown. Ghrelin mRNA had positive effects on the damaged cartilage, including reduced cartilage breakdown, limited abnormal thickening of bone, lowered inflammatory signals and decreased activation of pain-related nerve pathways.
This novel platform offers a simple, effective and automatically adjustable method for facilitating targeted RNA delivery. Although the current study utilized ghrelin mRNA, there is potential for the nanoparticles to support other RNA-based treatments, with the researchers commenting, “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.”
To be able to translate this approach to the clinic, however, more research is necessary. Next, the multi-institutional team plans to investigate how long the therapeutic effects of the nanoparticle treatments last, in addition to testing the delivery of different RNA therapies. They also want to apply the method within larger preclinical models that better mimic human knee joints.