Epigenetic metabolite lipid nanoparticles alleviate venous thrombosis via bone marrow reprogramming

Targeting coagulation cascade is a mainstay approach to therapy of thrombosis. One of the most prevalent complications of anticoagulation is a significant bleeding risk that can result in hospitalization. Recent studies on immunothrombosis (i.e. inflammation-linked thrombosis) proposed myeloid cells, especially neutrophils, to actively participate in thrombus formation through neutrophil extracellular traps (NETosis) and activation of inflammatory pathways. Here, we developed lipid nanoparticles (LNPs) with coagulation cascade-independent action that target neutrophils to alleviate venous thrombosis. A single intravenous dose of immunomodulatory metabolite itaconate (ITA)-bearing LNPs (ITA-LNPs) targeted >90% of bone marrow-resident neutrophils, but not macrophages or T lymphocytes. ITA-LNPs significantly diminished inflammation in cultured neutrophils and macrophages and improved survival in the mouse model of endotoxemia. When tested in an inferior vena cava ligation model of deep vein thrombosis, ITA-LNPs decreased the size and weight of thrombi as compared to control LNPs (Ctrl-LNPs). In addition, the thrombi from ITA-LNPs injected mice had significantly reduced neutrophil infiltration, decreased NETosis and interleukin-1 beta (IL-1β) expression. Intriguingly, one of the mechanisms through which this occurred was histone H4K12ac deacetylation, resulting in chromatin condensation and transcriptional repression of inflammatory genes and transcription factors involved in DNA damage response. Finally, we found that ITA-LNPs were hemostatically safe and neither targeted nor activated platelets in vivo. In sum, our work explores an LNP technology with an epigenetic mode of action serving as an anti-immunothrombotic therapy that could improve clinical outcomes without additional hemorrhagic risk.