SUMMARY Atherosclerotic plaque regression as a result of lipid-lowering treatment has been limited at best, with coronary artery disease (CAD) related event rates remaining unacceptably high. In this application, we propose that targeted immunomodulation of macrophages will resolve plaque inflammation and beneficially impacts myocardial infarction-induced monocytosis? detrimental effects. To that aim, we have developed novel ?nanobiologic?, a bioengineered version of our body?s own high density lipoprotein (HDL) nanoparticle that specifically targets (plaque) myeloid cells6,7. The HDL nanobiologic contains a small molecule inhibitor (TRAF6i), directed against the binding domain of CD40 on TRAF6, to specifically block CD40-TRAF6 interactions. Based on these preliminary data in Apoe?/? mice and nonhuman primates, we propose ? in two independent Specific Aims ? TRAF6i-HDL?s application to (i) prevent atherosclerotic plaque aggravation due to myocardial infarction in Apoe?/? mice and (ii) induce plaque regression in a nonhuman primate atherosclerosis model. In Aim 1, we will execute a longitudinal and imaging-guided therapeutic study, involving a one-week high-dose and a four-week low-dose TRAF6i-HDL regimen in atherosclerotic Apoe?/? mice. In the same mouse model, we will apply TRAF6i-HDL nano-immunotherapy to prevent plaque aggravation after myocardial infarction, by preventing the detrimental accumulation of inflammatory monocytes in the vessel wall. In Aim 2, based on our extensive mouse efficacy data and imaging data in nonhuman primates, we will employ TRAF6i-HDL nano- immunotherapy to regress established plaques in nonhuman primates. Positron emission tomography with magnetic resonance imaging (PET/MRI) methods will serve as readouts for TRAF6i-HDL?s in vivo behavior and therapeutic efficacy. In light of the promising CANTOS trial data, demonstrating a reduction in recurrent rates in cardiovascular patients that were treated with a targeted anti-inflammatory therapy, successful completion of this application?s aims will pave the way for potential clinical translation.