Macrophage-targeted single walled carbon nanotubes stimulate phagocytosis via pH-dependent drug release

Atherosclerotic cardiovascular disease is the leading cause of mortality in the world. A driving feature of atherosclerotic plaque formation is dysfunctional efferocytosis. Because the "don’t eat me" molecule CD47 is upregulated in atherosclerotic plaque cores, CD47-blocking strategies can stimulate the efferocytic clearance of apoptotic cells and thereby help prevent the progression of plaque buildup. However, these therapies are generally costly and, in clinical and murine trials, they have resulted in side effects including anemia and reticulocytosis. Here, we developed and characterized an intracellular phagocytosis-stimulating treatment in the CD47-SIRPα pathway. We loaded a novel monocyte/macrophage-selective nanoparticle carrier system with a small molecule enzymatic inhibitor that is released in a pH-dependent manner to stimulate macrophage efferocytosis of apoptotic cell debris via the CD47-SIRPα signaling pathway. We demonstrated that single-walled carbon nanotubes (SWNTs) can selectively deliver tyrosine phosphatase inhibitor 1 (TPI) intracellularly to macrophages, which potently stimulates efferocytosis, and chemically characterized the nanocarrier. Thus, SWNT-delivered TPI can stimulate macrophage efferocytosis, with the potential to reduce or prevent atherosclerotic disease.