Endothelium-targeted and untargeted nanoparticle therapies in thromboinflammatory vascular diseases

Endothelial cells (ECs) line the vasculature and integrate hemodynamic, inflammatory, and metabolic cues that are crucial in maintaining vascular health. Endothelial dysfunction is a driver of thromboinflammatory conditions including atherosclerosis, thrombosis, stroke, and sepsis-induced multiorgan dysfunction syndrome. Therapies for these conditions that are given systemically fail to target the site of disease and can be associated with off-target side effects. EC-targeted nanoparticles represent a novel method of concentrating the drug- or gene-based therapy in ECs at the site of disease. Here, we describe studies of EC-directed nanoparticles in thromboinflammatory vascular diseases. We discuss challenges in the development of EC-targeted nanoparticle therapies, including issues with biosafety, delivery efficiency, scalability, and clinical translation. To target ECs, nanoparticle surfaces have been coated with ligand-directed antibodies or peptides against EC markers. EC targeting has also been achieved by coating nanoparticles with cell-mimicking membranes to leverage native homing pathways to sites of vascular injury. Stimuli-responsive nanoparticles have used EC or disease-specific cues to trigger drug release, for instance via reactive oxygen species or shear stress stimuli. EC-targeted nanoparticles extend the therapy circulation time, enhance drug accumulation at target sites, improve therapeutic efficacy, and reduce toxicity. In preclinical studies, EC-targeted nanoparticles have stabilized atherosclerotic plaques, degraded venous thrombi, and reduced cerebral infarct volume. Although EC-targeted nanoparticle therapies have not yet been approved for clinical use, advances in the design and safety of nanoparticles are narrowing the gap between experimental promise and clinical reality.