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Magnetic nanoparticles (MNPs) used in bio-application have accelerated the development of “theranostics” which contains imaging, therapy and drug delivery. However, in a protein-rich physiological fluid, MNPs are ineluctable to a contact with protein to form “protein corona”, which will significantly change the physicochemical properties of the particles and their biological behavior. Therefore, we investigated the influence of protein and static magnetic field (SMF) on the cytotoxicity and cellular uptake of MNPs. The Fe₃O₄ nanoparticles (Fe₃O₄ NPs) were synthesized by solvothermal method with a mean diameter of $\sim 100$nm functionalized with carboxyl groups. After a period of 12h incubation in complete medium (CM), the wrapping of the Fe₃O₄ NPs by protein adsorption resulted in about 40-nm increase of the hydrodynamic size. Their stability in CM and water solution did not broaden significantly over time, which is exactly opposite in serum-free media (SFM). When transferred to SFM with high ionic-strength, the Fe₃O₄ NPs aggregated and settled quickly. We explore that the cell viability was decreased in proportion to the concentration and incubating time of Fe₃O₄ NPs, the absence of FBS and the presence of SMF exposure, respectively. Quantitative analysis showed that cells could incorporate more NPs in SFM, about five-fold more than in CM. In addition, it is obvious that exposure to SMF resulted in more cellular uptake both in CM and SFM. Our results demonstrated that Fe₃O₄ NPs in SFM and SMF exposure would settle down to cell rapidly, which caused more cellular uptake and higher cytotoxicity.

Nanoparticles, after incubation in biological fluids, adsorb several kinds of biomolecules like lipids, sugars and mainly proteins with high affinities for the nanoparticle surface and with long residence time, forming the so-called hard corona. The biological machinery, such as cellular barriers and membrane receptors can directly engage with the protein corona while the pristine surface may remain inaccessible. Here we isolate nanoparticles associated with strongly bound biomolecules from the unbound and loosely bound ones, by different approaches: centrifugation, size exclusion chromatography and magnetic isolation. The different separation methodologies, despite requiring diverse time and operating mechanisms, gave nanoparticle-hard corona complexes which were found to be remarkably similar in both dispersion properties and protein composition thus proving to be equally valid.

This article discusses the role of the protein corona in delivery systems with tagged nanoparticles and how knowledge of the protein corona can help in optimizing delivery. The basic question is whether and how the binding of proteins and other biomolecules at the nanoparticle surface interfere with the interaction between a tag and its receptor. This is an interesting problem in many respects, but most intriguing are the observed differences in delivery efficiency in vivo compared with protein-free in vitro conditions. In order to understand possible situations that the nanoparticle will face in a protein-rich biological environment, we will first describe the formation of a protein corona and thereafter discuss potential perturbations of the delivery systems when moving from in vitro testing to in vivo applications. We emphasize the role of mathematical modeling in optimizing the design of functionalized nanoparticles to achieve high success of delivery.