Particulate matter (PM) poses a significant risk to human health; however, it remains uncertain which size fraction is especially harmful and what mechanisms are involved. We investigated the varying effects of particle size on specific organ systems using a custom mouse exposure system and synthetic PM (SPM). Whole-body exposure of mice showed that micrometer-sized fine SPM (2-4 μm) accumulated in the lungs, the primary entry organ, while nanometer-sized SPM (<250 nm) did not accumulate, suggesting a transition into circulation. Mice exposed to micro-SPM exhibited inflammation and NADPH oxidase-derived oxidative stress in the lungs. In contrast, nano-SPM-exposed mice did not display oxidative stress in the lungs but rather at the brain, heart, and vascular levels, supporting the hypothesis that they penetrate the lungs and reach the circulation. Sources of reactive oxygen species from micro-SPM in the lung are NOX1 and NOX2, driven by pulmonary inflammation, while oxidative stress from nano-SPM in the heart is mediated by protein kinase C-dependent p47 phosphorylation, leading to NOX2 activation in infiltrated monocytes. Endothelial dysfunction and increased blood pressure were more pronounced in nano-SPM-exposed mice, also supported by elevated endothelin-1 and reduced endothelial nitric oxide synthase expression, which enhances constriction and diminishes vasodilation. Further, we estimated the cardiovascular disease burden of nano-particles in humans based on global exposure data and hazard ratios from an epidemiological cohort study. These results provide novel insights into the disease burdens of inhaled nano- and micro-particles (corresponding to fine and ultrafine categories), guiding future studies.