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Macrophage-Targeted Single Walled Carbon Nanotubes Stimulate Phagocytosis via pH-dependent Drug Release
Yapei Zhang1,2, Jianqin Ye3, Niloufar Hosseini-Nassab4
1Department of Biomedical Engineering, Michigan State University, East Lansing, MI, 48824 USA.
Insights
A novel nanoparticle delivers an inhibitor to macrophages, enhancing their ability to clear cellular debris. This approach may offer a new strategy to combat atherosclerotic cardiovascular disease without the side effects of current therapies.
Area of Science:
- Cardiovascular Science
- Nanomedicine
- Immunology
Background:
- Atherosclerotic cardiovascular disease is a leading global cause of mortality.
- Dysfunctional efferocytosis, the process by which cells are cleared, drives atherosclerotic plaque formation.
- The CD47 molecule, upregulated in plaques, inhibits efferocytosis, while CD47-blocking therapies cause side effects like anemia.
Purpose of the Study:
- To develop and characterize an intracellular phagocytosis-stimulating treatment targeting the CD47-SIRPα pathway.
- To create a novel nanoparticle system for targeted delivery of an efferocytosis-stimulating agent to macrophages.
- To evaluate the potential of this new therapy in preventing or reducing atherosclerotic disease progression.
Main Methods:
- Development of a monocyte/macrophage-selective nanoparticle carrier system.
- Loading the nanoparticle with a pH-dependent, small molecule enzymatic inhibitor (tyrosine phosphatase inhibitor 1 - TPI).
- Utilizing single-walled carbon nanotubes (SWNTs) for intracellular delivery of TPI to macrophages and chemical characterization of the nanocarrier.
Main Results:
- Demonstrated selective intracellular delivery of TPI to macrophages via SWNTs.
- Showcased that SWNT-delivered TPI potently stimulates macrophage efferocytosis.
- Confirmed the chemical characteristics of the SWNT nanocarrier system.
Conclusions:
- SWNT-delivered TPI effectively stimulates macrophage efferocytosis.
- This novel intracellular approach offers a potential alternative to CD47-blocking therapies for atherosclerotic disease.
- The therapy has the potential to reduce or prevent atherosclerotic disease progression with potentially fewer side effects.
Abstract:
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.
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