Intracellular delivery of anti-PECAM/SOD inhibits proinflammatory signaling of superoxide anion produced in endothelial endosomes in response to inflammatory mediators. Elevated generation of superoxide by endothelial enzymes including NADPH-oxidase is implicated in vascular oxidative stress and endothelial pro-inflammatory activation leading to exposure of VCAM-1. Anti-PECAM conjugated SOD and catalase bind specifically to endothelium and inhibit effects of their ROS substrates. Anti-PECAM/SOD, but not anti-PECAM/catalase or non-targeted enzymes including PEG-SOD, inhibited VCAM expression caused by tumor necrosis factor (TNF), interleukin-1β, and LPS. Anti-PECAM/SOD, but not non-targeted counterparts, accumulated in vascular endothelium after intravenous injection, localized in endothelial endosomes and inhibited LPS-caused VCAM-1 expression in mice. Anti-PECAM/SOD colocalized with EEA-1 positive endosomes and quenched ROS produced in response to TNF. Anti-PECAM/SOD even more effectively abolished VCAM expression caused by poly(I:C)-induced activation of toll-like receptor 3 localized in intracellular vesicles. Site-specific interception of endosomal superoxide attained by targeted delivery of anti-PECAM/SOD into endothelial endosomes may have anti-inflammatory effects. Schematic representation of proposed action of anti-PECAM/SOD entering endothelial cells via CAM-endocytosis on pro-inflammatory activation via plasmalemma TNF receptor internalized via caveolar endocytosis (left) and intracellular TLR3 (right). Binding of cytokine to cell surface receptors induces a cascade of events including endocytosis of receptor-ligand complexes via caveolar pathway and inflammatory activation. TLR3 involved in anti-viral defense localized in intracellular vesicles is activated upon the ligand endocytosis via clathrin-mediated endocytosis. Anti-PECAM/SOD enters cells via CAM-medicated endocytosis, and apparently traffics to these specific types of signaling endosomes. For details and explanations, please see Shuvaev et al. [199].