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Particulate carriers proposed for use in vascular-targeting are typically spherical and on the nanometer to sub-micron scale. However, spherical nanoparticles do not efficiently marginate, or localize to the cell-free layer (CFL), in blood flow making them sub-optimal as vascular-targeted carriers. Microspheres with diameter ≥ 2 µm are able to efficiently marginate in the presence of blood, however may present issues in navigating the vasculature or in adhering in the presence of high shear forces. Here, we investigate how physical design parameters in addition to particle size, namely particle shape and density, affect the efficacy of vascular-targeted carriers (VTC) both in vitro and in vivo. We find that particle shape and density both affect the ability of microparticles to adhere to inflamed endothelium from blood flow. Rod and disk-shaped particles display improved adhesion in vitro to endothelium compared to equivalent spheres, provided the aspect ratio is sufficiently high and the equivalent spherical diameter (ESD) is ≥ 1 µm. These effects were confirmed in vivo, as targeted 2 µm ESD rods bound to the aorta of atherosclerotic mice at levels ~3 times higher than equivalent spheres, while 500 nm rods and spheres displayed minimal adhesion. We also find that particle density affects the ability of nanoparticles (500 nm diameter) to target inflamed endothelium. Silica spheres (2.0 g/cm3) adhered to inflamed endothelium in vitro at consistently higher levels than either polystyrene (1.05 g/cm3) or titania (3.9 g/cm3) spheres, while titania spheres only display improved adhesion when external forces (such as gravity, centrifugal force) also favor adhesion. Particle density also affected the adhesion profile along the aorta of mice with systemic inflammation, with silica spheres displaying the most adhesion. Overall this work shows that particle shape and density are design parameters which should be considered to optimize the performance of vascular-targeted carriers.