Nanoparticles (NPs) represent one of the most promising tools for drug-targeting and drug-delivery. However, a deeper understanding of the complex dynamics that happen after their in vivo administration is required. Particularly, plasma proteins tend to associate to NPs, forming a new surface named the 'protein corona' (PC). This surface is the most exposed as the 'visible side' of NPs and therefore, can have a strong impact on NP biodistribution, targeting efficacy and also toxicity. The PC consists of two poorly delimited layers, known as 'hard corona' (HC) and 'soft corona' (SC), that are affected by the complexity of the environment and the formed protein-surface equilibrium during in vivo blood circulation. The HC corona is formed by proteins strongly associated to the NPs, while the SC is an outer layer consisting of loosely bound proteins. Several studies attempted to investigate the HC, which is easier to be isolated, but yielded poor reproducibility, due to varying experimental conditions. As a consequence, full mapping of the HC for different NPs is still lacking. Moreover, the current knowledge on the SC, which may play a major role in the 'first' interaction of NPs once in vivo, is very limited, mainly due to the difficulties in preserving it after purification. Therefore, multi-disciplinary approaches leading to the obtainment of a major number of information about the PC and its properties is strongly needed to fully understand its impact and to better support a more safety and conscious application of nanotechnology in medicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1467. doi: 10.1002/wnan.1467 For further resources related to this article, please visit the WIREs website.
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