Development of\nPro-resolving and Pro-efferocytic Nanoparticles\nfor Atherosclerosis Therapy

Atherosclerosis is a major contributor to cardiovascular\ndiseases\nwith a high global prevalence. It is characterized by the formation\nof lipid-laden plaques in the arteries, which eventually lead to plaque\nrupture and thrombosis. While the current lipid-lowering therapies\nare generally effective in lowering the risk of cardiovascular events,\nthey do not address the underlying causes of disease. Defective resolution\nof inflammation and impaired efferocytosis are the main driving forces\nof atherosclerosis. Macrophages recognize cells for clearance by the\nexpression of “eat me” and “do not eat me”\nsignals, including the CD47-SIRPα axis. However, the “do\nnot eat me” signal CD47 is overexpressed in atherosclerotic\nplaques, leading to compromised efferocytosis and secondary necrosis.\nIn this context, prophagocytic antibodies have been explored to stimulate\nthe clearance of apoptotic cells, but they are nonspecific and impact\nhealthy tissues. In macrophages, downstream of signal regulatory protein\nα, lie protein tyrosine phosphatases, SHP 1/2, which can serve\nas effective targets for selectively phagocytosing apoptotic cells.\nWhile increasing the efferocytosis targets the end stages of lesion\ndevelopment, the underlying issue of inflammation still persists.\nSimultaneously increasing efferocytosis and reducing inflammation\ncan be effective therapeutic strategies for managing atherosclerosis.\nFor instance, IL-10 is a key anti-inflammatory mediator that enhances\nefferocytosis via phosphoSTAT3 (pSTAT3) activation. In this study,\nwe developed a combination nanotherapy by encapsulating an SHP-1 inhibitor\n(NSC 87877) and IL-10 in a single nanoparticle platform [(S + IL)-NPs]\nto enhance efferocytosis and inflammation resolution. Our studies\nsuggest that (S + IL)-NPs successfully encapsulated both agents, entered\nthe macrophages, and delivered the agents into intracellular compartments.\nAdditionally, (S + IL)-NPs decreased inflammation by suppressing pro-inflammatory\nmarkers and enhancing anti-inflammatory mediators. They also exhibited\nthe potential for improved phagocytic activity via pSTAT3 activation.\nOur nanomedicine-mediated upregulation of the anti-inflammatory and\nefferocytic responses in macrophages shows promise for the treatment\nof atherosclerosis.