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Nanoparticles are promising drug delivery systems to overcome physiological barriers such as the blood-brain barrier. In this respect nanoparticle uptake into endothelial or epithelial cells is the first necessary step to overcome these obstacles. Therefore, a new strategy for the covalent attachment of drug targeting ligands on poly(lactic acid) (PLA) nanoparticles was developed and the influence of the resulting surface properties on the uptake behaviour in cerebral endothelial cells was investigated. PLA nanoparticles were modified on their surface by apolipoprotein E, penetratin, or ovalbumin using a newly developed vinyl sulfone-modified poly(vinyl alcohol)-derivative (VS-PVA) as steric stabilizer. With this approach an easy option for ligand coupling reactions to PVA-stabilized nanoparticles was achieved. All obtained formulations showed a favourable behaviour concerning cytotoxic effects on endothelial cells, not compromising their viability. Furthermore, a clear relation between cellular uptake and surface coupled functional ligand could be determined: Penetratin- and apolipoprotein E-modified nanoparticles showed a distinct higher cellular uptake than ovalbumin-modified or unmodified nanoparticles, which both can be explained by mechanistic reasons. Overall the use of the reactive VS-PVA as stabilizer for nanoparticle preparation is an universal and effective approach to couple several functional ligands to the particles' surface for targeting applications.