LAUSR

After intravenous administration of nanocarriers, plasma proteins may rapidly adsorb onto their surface. This process hampers the prediction of the nanocarriers' pharmacokinetics as it determines their physiological identity in a complex biological environment. Towards clinical translation it is therefore an essential prerequisite to investigate the nanocarriers' interaction with plasma proteins. Here, we evaluated a highly "PEGylated" squaric ester-based nanogel with inherent prolonged blood circulation properties. After incubation with human blood plasma, we isolated the nanogels by asymmetrical flow-field flow fractionation (AF4). Multiangle light scattering measurements confirmed the absence of significant size increases as well as aggregation upon plasma incubation. However, proteomic analyses by gel electrophoresis found minor absolute amounts of proteins (3 wt%), whereas label-free liquid chromatography mass spectrometry (LC-MS) identified 65 enriched proteins. Interestingly, the relative abundance of these proteins was almost similar to their proportion in pure native plasma. Due to the nanogels' hydrated and porous network morphology, we concluded that the detected proteins rather result from a passive diffusion into the nanogel network than from specific interactions at the plasma particle interface. Consequently, these results do not indicate a classical surface protein corona but rather reflect the highly outer and inner stealth-like behavior of the porous hydrogel network of "PEGylated" nanogels. This article is protected by copyright. All rights reserved.