Advances in nucleic acid architectures for electrochemical sensing

Nucleic acid–based electrochemical sensors are ideally suited to the detection of molecular targets for which enzymatic detection or direct electrochemical oxidation – reduction reactions are not possible. Moreover, the versatility of nucleic acids in their ability to bind a great variety of target types, from small molecules to single-entity mesoscopic targets, makes them attractive receptors for the development of electrochemical biosensors. In this brief opinion piece, we discuss field advances from the past two years. We hope the works highlighted here will inspire the community to pursue creative designs enabling the detection of larger and more complex targets with a specific focus on analytical validation and translation into preclinical or clinical applications.     

A Biomimetic Phosphatidylcholine-Terminated Monolayer Greatly Improves the In Vivo Performance of Electrochemical Aptamer-Based Sensors

The real-time monitoring of specific analytes in situ in the living body would greatly advance our understanding of physiology and the development of personalized medicine. Because they are continuous (wash-free and reagentless) and are able to work in complex media (e.g., undiluted serum), electrochemical aptamer-based (E-AB) sensors are promising candidates to fill this role. E-AB sensors suffer, however, from often-severe baseline drift when deployed in undiluted whole blood either in vitro or in vivo. We demonstrate that cell-membrane-mimicking phosphatidylcholine (PC)-terminated monolayers improve the performance of E-AB sensors, reducing the baseline drift from around 70 % to just a few percent after several hours in flowing whole blood in vitro. With this improvement comes the ability to deploy E-AB sensors directly in situ in the veins of live animals, achieving micromolar precision over many hours without the use of physical barriers or active drift-correction algorithms.     

The challenge of long-term stability for nucleic acid-based electrochemical sensors

Nucleic acid-based electrochemical sensors are a versatile technology enabling affinity-based detection of a great variety of molecular targets, regardless of inherent electrochemical activity or enzymatic reactivity. Additionally, their modular interface and ease of fabrication enable rapid prototyping and sensor development. However, the technology has inhibiting limitations in terms of long-term stability that have precluded translation into clinically valuable platforms like continuous molecular monitors. In this opinion, we discuss published methods to address various aspects of sensor stability, including thiol-based monolayers and anti-biofouling capabilities. We hope the highlighted works will motivate the field to develop innovative strategies for extending the long-term operational life of nucleic acid-based electrochemical sensors.