The cellular arm, in particular monocytes and their lineage descendant macrophages, participate critically in inflammatory activity in major diseases. Our understanding of the innate immune system's role in homeostasis and disease has considerably expanded over the last decades. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.
Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Inflammatory monocytes - but not the non-inflammatory subset - depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression.
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