Protein corona as the key factor governing the <i>in vivo</i> fate of magnetic nanoparticles

Advancements in the field of nanotechnology have opened a myriad of avenues for diverse applications. One such avenue is the role of nanoparticles (NPs) in the healthcare sector, whether it is drug targeting, drug delivery, or imaging, offering unprecedented prospects for improving targeted interventions along with minimal toxicity. Meanwhile, the intricate interplay between the characteristics of NPs and the ensuing biological cross-talk has engendered profound interest among scientists. Amidst the determinants shaping the behavior of NPs within the biological milieu, the biodistribution and pharmacokinetics of the NPs stand as pivotal factors intricately intertwined with their core size, hydrodynamic diameter (HD), coating ligands, as well as the proteins they interact with, forming the protein corona. This article compiles and analyzes the data to decipher the factors determining the fate of NPs <i>in vivo</i>. For this purpose, two IONPs with differing core sizes (≈4 nm and ≈8 nm) but coated with the same gallol-PEG ligand (GA-PEG3000-OH) and possessing very similar HDs (≈35 nm) as well as relaxivity (≈100 mM^-1 s^-1) were selected. Following physicochemical characterization, both protein coronas were thoroughly analyzed, revealing differences in both the composition and the relative abundance. Later, after determining the negligible cytotoxicity of both NPs, they were intravenously injected into Balb/c mice to evaluate their <i>in vivo</i> biodistribution and pharmacokinetics using MRI. Additionally, biodistribution was further investigated <i>ex vivo</i> by quantitative magnetic analysis of blood and tissues, alongside histological evaluation. Our results evidenced that the protein corona, rather than core size or hydrodynamic diameter, is the determining factor governing the <i>in vivo</i> fate of magnetic NPs.