Researchers from Stanford University and Michigan State University have teamed up to create a nanoparticle that can eat away at the arterial plaques that lead to strokes and heart attacks in a mouse model of atherosclerosis.
The team has created a nanoparticle that acts like a Trojan horse, targeting atherosclerotic plaque to reduce its amount and prevent it from getting out of control. A considerable amount of plaque material consists of dead and dying macrophages, a type of immune cell, which have become trapped and overwhelmed while trying to remove debris and fatty deposits. As these cells die, they attract more macrophages which arrive to try to clear up the waste; they too become trapped, and this is the foundation of atherosclerotic plaque.
The new study demonstrates how the nanoparticle is able to locate the plaque while showing high selectivity for macrophages . Once it has located its target, the nanoparticle enters the macrophages within the plaque and delivers a drug payload to the cells, encouraging the macrophages to engulf and consume cellular debris. Essentially, this means that the macrophages eat the dead and dying cells within the plaque and thus reduce its overall size.
The approach is based on blocking macrophage signaling and giving them new instructions through the small molecules delivered in the payload. Unlike approaches that attempt to target the receptors on the cell surface, this approach does so from within the cell itself and has so far proven effective in modifying macrophage behavior.
The researchers are now planning to translate their approach to large animal models and human tissues on the road to clinical trials.
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.
Novel delivery systems to address diseases such as atherosclerosis have great potential and, if successful, could put an end to one of the biggest causes of death worldwide. While this approach is likely quite a few years away before it reaches human trials, it still gives an indication of how innovative and novel therapies are being developed and how approaches to age-related diseases are changing.
 Flores, A. M., Ye, J., Hosseini-Nassab, N., Jarr, K. U., Zhu, X., Smith, B. R., & Leeper, N. J. (2019). Efferocytosis-stimulating Nanoparticles for Precision Atherosclerosis Therapy. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(Suppl_1), A142-A142.