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 nano-bio interactions. Accordingly, the characterization of PC includes the analysis of the formation process and mechanisms of PC; it also involves the analysis of the effects of PC on the properties of the NMs and proteins. The formation of PC is not conducive to the application of NMs in vivo. To overcome the adverse effects of PC, the design of active regulatory strategies, including the regulation of its content, composition, and structure, is garnering attention in the nanomedicine field. Thus, it is necessary to systematically establish the relationship among NMs, PCs, and biological effects, which will help in predicting and controlling the fate of in vivo nanomedicine, thereby assisting in designing safer and more effective nanomedicine. In this review, factors affecting the formation of PC, analytical methods, and biological effects of PC are thoroughly discussed. Additionally, new strategies to actively manipulate PC to assist in nanomedicine design are emphasized. Finally, we summarize the problems and challenges in PC studies and propose possible strategies.

Automated summary

The potential of nanomaterials (NMs) in treating diseases and mitigating toxicity has led to increased research and development in this field. However, the synthesis technology of most NMs is still in the early stage, resulting in a disconnect between industry and research. The formation of protein corona (PC) on the surface of NMs has a significant impact on their physicochemical properties and biological effects. Understanding the formation and influence of PC, as well as designing active regulation strategies, is crucial for the safe and effective design of nanomedicine.