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Nanoparticles have numerous biomedical applications including drug delivery, therapies, bone implants, disease dignosis and imaging. Therefore, the interaction between the nanoparticles and biological systems becomes vital to understand, for their safe and effective applications. A protein corona is formed when proteins existing in biological systems cover a nanoparticle's surface. The alteration of size and interfacial composition of nanoparticles results in new biological characteristics and influences the circulation lifetime, accumulation, toxicity, cellular uptake and agglomeration, depending on the composition of the nanoparticle protein corona. This chapter presents comprehensive information about the various factors affecting the nanoparticle–protein interaction including the physicochemical properties of the nanoparticles (size, shape, surface charge, surface functional group, hydrophilicity/hydrophobicity), the nature of the biological medium and the exposure time and the temperature. Understanding these factors will allow us to design safe nano-constructs for biomedical applications.

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