Atherosclerosis is the generation of fatty deposits in blood vessel walls, called plaques, atheromas, or lesions, that narrow and weaken important vessels. Sooner or later a vessel ruptures, or a plaque disintegrates and its fragments block the flow of blood, and this results in stroke or heart attack. In the public eye atherosclerosis is considered a disease of cholesterol, of blood lipids, and reducing cholesterol and other lipids in the blood remains the primary focus of treatment. This is despite the fact that this approach can only slow progression - it doesn't reverse existing lesions to a sizable degree.
Atherosclerosis is in fact a condition of macrophage dysfunction, not of cholesterol. Macrophages are the cells responsible for clearing out lipids from blood vessel walls. They ingest cholesterol, and then hand it off to HDL particles that can carry it back to the liver for excretion. This process works just fine in youth, but macrophages are unfortunately vulnerable to oxidized cholesterol. It makes them dysfunctional, inflammatory, and even kills them. As a result of other forms of age-related damage, such as mitochondrial dysfunction, levels of oxidized cholesterol increase significantly. A feedback loop forms in which macrophages are constantly drawn to a lesion, succumb to the oxidized cholesterol present there, and add their corpses to the growing deposit. Atherosclerotic lesions are macrophage graveyards.
Thus macrophages are, to my eyes, the right point of intervention for therapies to effectively treat atherosclerosis - to actually prevent and meaningfully reverse lesions. This might be achieved by making macrophages invulnerable to the oxidized cholesterol that challenge them, as Repair Biotechnologies is working towards, or by clearing out oxidized cholesterols, as Underdog Pharmaceuticals is working towards. The research noted here takes a different view of the opportunities presented by a tissue that is rich in macrophages, and reports on a way to force those macrophages to more aggressively clear debris and destroy harmful cells in a lesion, despite their impediments. The initial data seems promising.
Researchers have demonstrated a nanoparticle that homes in on atherosclerotic plaque due to its high selectivity to a particular immune cell type - monocytes and macrophages. Once inside the macrophages in those plaques, it delivers a drug agent that stimulates the cell to engulf and eat cellular debris. Basically, it removes the diseased/dead cells in the plaque core. By reinvigorating the macrophages, plaque size is reduced and stabilized.
The research is focused on intercepting the signaling of the receptors in the macrophages and sending a message via small molecules using nano-immunotherapeutic platforms. Previous studies have acted on the surface of the cells, but this new approach works intracellularly and has been effective in stimulating macrophages. "We found we could stimulate the macrophages to selectively eat dead and dying cells - these inflammatory cells are precursor cells to atherosclerosis - that are part of the cause of heart attacks. We could deliver a small molecule inside the macrophages to tell them to begin eating again."
Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia.
Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs.
Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.