First, we discuss peptide-based and antibody (Ab)-based nanoparticles utilized for diagnostic, therapeutic, and theranostic applications. variability between animals and among models used is usually a barrier to reproducible results and comparability of NP efficacy. cultures isolate cells into microenvironments that fail to take into account circulation separation and shear stress, which are characteristics of atherosclerotic lesions. Flow-based models provide more physiologically relevant platforms, bridging the space between and 2D models. This is the HSF1A first review that presents recent advances regarding endothelial HSF1A cell-targeting using adhesion molecules in light of and flow-based models, providing insights for future development of optimal strategies against atherosclerosis. and atherosclerotic models.30C33 The treatment of atherosclerosis is often limited by the lack of understanding regarding the interplay between the NP and the endothelium. models provide a platform that includes all the parameters in a physiologically functional system, which usually suggests clinical relevance. However, the CREB3L4 ethical issues and high costs associated with the use of animals and the inherent variable nature between individual specimens are barriers to repeatable results and comparability of NP efficacy. At the other end of the spectrum are highly controlled 2D cell cultures, which pressure cells into isolation and do not provide a physiologically relevant microenvironment. circulation models can close the space between 2D cell culture and animal experiments, providing additional parameters such as shear stress, 3D architecture, and co-culture conditions. In this review, current targeted strategies using NPs are reviewed, focusing on targeting moieties that enable NP localization to activated ECs expressing VCAM-1 as well as other major CAMs. We first discuss recent developments of diagnostic and therapeutic NPs targeting ECs using peptides and Abs in models (Table 1). The second half of this review focuses on the flow models that have been specifically developed for evaluating the targeting efficiency of particles to the endothelium using CAMs, as well as models investigating CAM expression and leukocyte recruitment in response to disturbed flow conditions. Table 1 Nanoparticles targeting cell adhesion cells for diagnostic, therapeutic, and theranostic applications in atherosclerotic-related diseases models and CAMs expression Peptide-based nanomaterials for targeting VCAM in?vivo VCAM-1 is an adhesion molecule that is overexpressed around the surfaces of inflamed ECs in atherosclerosis.34,35 VCAM-1 acts as a mediator in the recruitment of monocytes to the plaque.31 It plays a critical role in the inflammatory process and its expression is often correlated with the progression of atherosclerotic lesions. For these reasons, VCAM-1 expression is usually a reliable target to consider in the development of several imaging tools and therapies against atherosclerosis. One strategy to incorporate a biomarker for cell-specific binding and localization is usually by modifying the surface of NPs with peptides. Peptide-based nanomaterials provide greater selectivity than free drugs, therefore limiting the potential off-target side effects generally associated with small molecule targeting.36 Due to their ability to form secondary structures, such as helices and coils, peptides can be presented on the exterior of the NP for active targeting.37 In addition, their small size offers enhanced penetration into HSF1A tissues over whole proteins.36 Recent efforts have been directed toward enhancing diagnostic methods to detect vulnerable, atherosclerotic plaques prone to rupturing, which can allow for earlier intervention and may ultimately reduce the numbers of heart attacks and strokes. A number of imaging modalities exist for vulnerable plaque detection, from optical imaging to magnetic resonance imaging (MRI). Kelly by MRI without the use of VCAM-1 Abs. Nahrendorf imaging in ApoE?/? mice. (a) to (d) 24-h post injection, control (not functionalized with a targeting moiety) PAMs mostly show a strong signal in the bladder and liver, but not in the aorta. (e) to (g) In contrast, VCAM-1-targeting PAMs localize in the cardiovascular system (denoted by arrow), primarily in the aorta. Adapted from Mlinar targeting show that (b) only autofluorescence signals were detected in the aorta of control mice. Scale bar: 500?m. (c) VCAM-1 staining (green) was strongly detected in the aorta of ApoE?/? mice (FITC-labeled secondary antibody). Blue is usually staining of cell nuclei by DAPI. Scale.