The problem. The last decade has seen unprecedented progress in understanding the immune processes that drive atherosclerotic lesion initiation, maturation and complication. In particular, macrophages emerged as key cells that promote disease progression. If the number of inflammatory macrophages in plaque increases, atherosclerosis advances towards life-threatening complications. Plaque macrophages derive from circulating monocytes, which in turn arise from myeloid progenitors and hematopoietic stem cells. When released into circulation, monocytes follow chemokine gradients towards atherosclerotic plaque, where endothelial adhesion molecules aid their extravasation into the vessel wall. Once in plaque, inflammatory macrophages destabilize matrix via proteases and may die locally. Alternatively, if the local environment permits, macrophages may obtain less inflammatory phenotypes promoting cholesterol removal and tissue repair. These insights have been difficult to translate into clinically useful therapeutics, partly because broad anti-inflammatory therapy may compromise beneficial functions of immune cells and host defense. The goal. In this application, we aim to create a new class of macrophage-targeted atherosclerosis therapeutics using in vivo RNA interference (RNAi). We will design small interfering RNA (siRNA) targeting discrete proteins which are key decision nodes for macrophages' fate. We propose to interfere with the life cycle of macrophages with the goal to support inflammation resolution in atherosclerotic plaque. We will test the central hypothesis that RNAi can be harnessed to design precision therapeutics for inflammatory atherosclerosis. We will test this hypothesis by targeting proteins that are essential for macrophage birth (silencing transcription factors MTG16 and PU.1 that influence activity of hematopoietic stem cells and endothelial targets in the hematopoietic niche), migration (silencing chemokine receptors in monocytes and adhesion molecules in endothelial cells), maturation (silencing the M-CSF receptor essential for differentiation of monocytes into macrophages) and polarization (silencing the essential transcription factor IRF5 that gives rise to M1 macrophages with inflammatory functions). Innovation. We will use new nanomaterials for delivery to myeloid, progenitor and endothelial cells, newly and yet-to-be identified siRNA sequences, and target innovative biological targets important in the macrophage life cycle. Impact. We will develop new therapeutics to dampen inflammatory macrophage activity in the arterial wall. We will identify a winning therapeutic strategy in mice with post-MI acceleration of atherosclerosis, a scenario that simulates the vulnerable patient in need of aggressive therapeutic intervention. Our ultimate goal is to bring these materials into the clinic, improving the currently insufficient standard of care by enabling better secondary prevention of myocardial infarction and stroke.