Researchers at the University of Illinois Chicago have devised a cure for pulmonary fibrosis that involves employing nanoparticles coated with mannose, a sugar, to prevent a group of lung cells called macrophages from contributing to lung tissue damage. The cell-targeting technique has the potential to avoid this life-threatening lung scarring condition, which can cause shortness of breath and other life-threatening problems.
The medication is not yet prepared for clinical trials, according to the researchers, but its efficacy in relevant animal models is a positive indicator that it may be possible to cure the condition, which now has relatively few and imprecise medicines.
The activation of damaging immune cells that induce excessive inflammation is a primary factor of lung fibrosis.
The body’s inflammatory processes are very complex and finding treatments for diseases that result from lingering or excessive inflammation is very difficult because the treatments that prevent harmful inflammation also, unfortunately, prevent helpful inflammation which fights infections and heals injuries. To have a targeted treatment that addressed a root cause of harmful inflammation work in an animal model is exciting.
Abhalaxmi Singh, Visiting Research Assistant Professor, Department of Pharmacology and Regenerative Medicine, UIC College of Medicine
The coated nanoparticle therapy inhibits fibrosis by attaching to a fraction of macrophages, which are white blood cells prevalent in all organs and have a mannose receptor. In patients with pulmonary fibrosis, this receptor, known as CD206, is overexpressed.
The researchers discovered that the macrophages that induce lung fibrosis have extremely high mannose levels. Macrophages undergo a transition in pulmonary fibrosis that produces cytokines and promotes scarring. Singh and her researchers examined the scar-promoting macrophages’ surfaces as well as the CD206 mannose receptor and created a nano-vehicle to approach these receptors.
When the sugar-coated nanoparticle attaches to the receptor on the cell, it releases the nucleotide — a piece of siRNA targeting transforming growth factor beta (TGFB) — that the scientists incorporated into the nanoparticle.
A cell signaling mechanism known to be implicated in pulmonary fibrosis is SiRNA targeting TGFB. Once within the cell, the nucleotide prevents macrophages from producing excessive amounts of proteins implicated in scar formation, such as collagen.
Macrophages are exciting, complex cells, and the approach Dr. Singh and our team took in coating the nanoparticle with sugar to bind to the mannose receptor is an intriguing and precise way to ensure targeted delivery of a silencing RNA treatment to this subset of cells that contribute to fibrosis.
Asrar Malik, Head, Department of Pharmacology and Regenerative Medicine, UIC College of Medicine
Malik was also the Schweppe Family Distinguished Professor.
With colleagues at the University of California, San Francisco, the team has already begun evaluating the treatment in human lung tissue samples.
The nanoparticles used in the trials are made from albumin, a protein that scientists are researching as a way to deliver treatments for several illnesses.
Malik’s team was the first to find that albumin nanoparticles may be employed in precision medicine to decrease inflammation. Their finding was first published in the journal Nature Nanotechnology in 2014.
The creators then founded Nano Biotherapeutics, an independent startup firm sponsored by a phase II Small Business Technology Transfer grant from the National Institutes of Health, to recruit the partners and investors required to bring the discovery to market.
Singh, A., et al. (2022) Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2121098119.