Nanoparticles (NPs) are versatile candidates for nanomedical applications due to their unique physicochemical properties. However, their clinical applicability is hindered by their undesirable recognition by the immune system and the consequent immunotoxicity, as well as their rapid clearance in vivo. After injection, NPs are usually covered with layers of proteins, called protein coronas (PCs), which alter their identity, biodistribution, half-life, and efficacy. Therefore, the characterization of the PC is for in predicting the fate of NPs in vivo. The aim of this review was to summarize the state of the art regarding the intrinsic factors closely related to the NP structure, and extrinsic factors that govern PC formation in vitro. In addition, well-known opsonins, including complement, immunoglobulins, fibrinogen, and dysopsonins, such as histidine-rich glycoprotein, apolipoproteins, and albumin, are described in relation to their role in NP detection by immune cells. Particular emphasis is placed on their role in mediating the interaction of NPs with innate and adaptive immune cells. Finally, strategies to reduce PC formation are discussed in detail.
