纳米医学中蛋白冠的化学和生物学性质及其调控策略

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

近年来,纳米生物医用材料的研发数量呈几何增长,但只有少数被批准在临床应用,产学研出现严重的脱节现象,这主要是由于目前对纳米材料与生物体相互作用的认知十分有限.纳米材料进入体内后,蛋白质等生物分子会不可避免地吸附在其表面形成蛋白冠(protein corona,PC),这成为纳米材料生物应用遇到的第一道生物屏障.蛋白冠的形成受到纳米材料的本征理化特性、生物流体性质以及环境因素等多方面的影响,会改变纳米材料的本征理化特性,并赋予其新的化学生物学特性,进而改变纳米材料的体内生物学行为,包括细胞摄取、免疫反应、血液循环、靶向、生物分布以及毒性等.因此,深入地理解蛋白冠的特性及其对纳米材料体内命运的影响是调控纳米材料有效性和安全性的重要科学基础.本文对蛋白冠的形成影响因素、分析方法以及产生的化学生物学效应进行了深入讨论,并强调了主动调控蛋白冠的含量、成分以及组织结构辅助纳米药物设计的新策略.最后,我们总结了目前在蛋白冠研究和认知方面存在的问题和挑战,并提出了解决方案.

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 tosynthesize most nanomaterials is still in the early stage, and only a few NMs are approved and clinically used. There is aserious disconnect between industry and research mainly due to the limited understanding of the dynamic and variation ininteractions 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 traffickingand secretion. After the administration of NMs, proteins and other biomolecules are deposited on their surfaces viaelectrostatic, van der Waals, or hydrophobic forces and form protein corona (PC), which is the first in vivo biological barrierencountered by NMs. The formation of PC is a dynamic, competitive, and complex process that is affected by thephysicochemical properties of NMs, characteristics of biological fluids, and environmental factors. PC modifies thephysicochemical properties of NMs and endows them with new biological identities, which determine the course of variousbiological events, such as cellular uptake, immune response, biodistribution, clearance, and toxicity. The characterizationof PC formation and its influence on NMs and proteins is the first step to thoroughly understanding complex nano-biointeractions. 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 notconducive to the application of NMs in vivo. To overcome the adverse effects of PC, the design of active regulatorystrategies, including the regulation of its content, composition, and structure, is garnering attention in the nanomedicinefield. Thus, it is necessary to systematically establish the relationship among NMs, PCs, and biological effects, which willhelp in predicting and controlling the fate of in vivo nanomedicine, thereby assisting in designing safer and more effectivenanomedicine.In this review, factors affecting the formation of PC, analytical methods, and biological effects of PC are thoroughlydiscussed. 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.