Macrophage-Drug Combo Nanoparticle Reduces and Stabilizes Atherosclerotic Plaque

Researchers from Michigan State University (MSU) and Stanford University say they have invented a nanoparticle that eats away—from the inside out—portions of plaques that cause heart attacks. Bryan Smith, PhD, associate professor of biomedical engineering at MSU, and a team of scientists created a nanoparticle that reportedly can be directed to eat debris, reducing and stabilizing plaque. The discovery could be a potential treatment for atherosclerosis, a leading cause of death in the United States, according to the researchers who published their study (“Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis”) in Nature Nanotechnology.

“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 anemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signaling axis,” the investigators wrote.

“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.

“The results showcase the nanoparticle that homes in on atherosclerotic plaque due to its high selectivity to 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,” explained Smith, who added that “future clinical trials on the nanoparticle are expected to reduce the risk of most types of heart attacks, with minimal side effects due to the selectivity of the nanodrug.”

Smith’s studies focus 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,” Smith said. “We could deliver a small molecule inside the macrophages to tell them to begin eating again.”

This approach also has applications beyond atherosclerosis, he added.

“We were able to marry a groundbreaking finding in atherosclerosis by our collaborators with the state-of-the-art selectivity and delivery capabilities of our advanced nanomaterial platform. We demonstrated the nanomaterials were able to selectively seek out and deliver a message to the very cells needed,” noted Smith. “It gives a particular energy to our future work, which will include clinical translation of these nanomaterials using large animal models and human tissue tests. We believe it is better than previous methods.”