The Challenges and Opportunities of Protein Coronas for Nanoscale Biomolecular Sensing

The unique benefits of sub-picomolar and single-molecule detection for the diagnosis and prognosis of diseases and therapeutic efficacy monitoring have been driving the development of nanoscale biomolecular sensors. Nanoscale sensors can be attached to the surface or dispersed in solution, enabling the rapid detection of analytes with high sensitivity and specificity by overcoming concentration-driven diffusion limits. In biological fluids, however, nanoscale objects are surrounded by biomolecules, mostly proteins, that form an evolving encapsulating surface layer, commonly known as the protein corona. The protein corona can modify the biosensor surface, which can adversely impact biosensing specificity, sensitivity, and accuracy. Conversely, the protein corona can be exploited to design biosensors for disease diagnostics, the discovery of new biomarkers, and environmental contaminants. In this review, the factors influencing protein corona formation on nanoscale biosensors are examined. Characterization methods and the effects of protein corona formation on the performance of nanoscale biosensors are also discussed. Promising strategies to prevent, circumvent, and exploit corona formation are presented and this review concludes by outlining future perspectives of nanoscale biomolecular sensors for practical application in biological fluids.