Chemical and biophysical characteristics of protein corona in nanomedicine and its regulatory strategies

Owing to the great potential of nanomaterials (NMs) to treat human diseases and mitigate the toxicity of engineered NMs, the research and development of NMs have geometrically increased. However, the development of technology to synthesize most nanomaterials is still in the early stage, and only a few NMs are approved and clinically used. There is a serious disconnect between industry and research mainly due to the limited understanding of the dynamic and variation in interactions between nanomaterials and biological microenvironments. NMs undergo multifaceted in vivo delivery processes after systemic administration, including circulation in the blood, distribution to tissues and organs, interactions with extracellular matrix components and cells, and intracellular trafficking and secretion. After the administration of NMs, proteins and other biomolecules are deposited on their surfaces via electrostatic, van der Waals, or hydrophobic forces and form protein corona (PC), which is the first in vivo biological barrier encountered by NMs. The formation of PC is a dynamic, competitive, and complex process that is affected by the physicochemical properties of NMs, characteristics of biological fluids, and environmental factors. PC modifies the physicochemical properties of NMs and endows them with new biological identities, which determine the course of various biological events, such as cellular uptake, immune response, biodistribution, clearance, and toxicity. The characterization of PC formation and its influence on NMs and proteins is the first step to thoroughly understanding complex