Development of the DNA-based biosensors for high performance in detection of molecular biomarkers: More rapid, sensitive, and universal

Abstract

The molecular biomarkers are molecules that are closely related to specific physiological states. Numerous molecular biomarkers have been identified as targets for disease diagnosis and biological research. To date, developing highly efficient probes for the precise detection of biomarkers has become an attractive research field which is very important for biological and biochemical studies. During the past decades, not only the small chemical probe molecules but also the biomacromolecules such as enzymes, antibodies, and nucleic acids have been introduced to construct of biosensor platform to achieve the detection of biomarkers in a highly specific and highly efficient way. Nevertheless, improving the performance of the biosensors, especially in clinical applications, is still in urgent demand in this field. A noteworthy example is the Corona Virus Disease 2019 (COVID-19) that breaks out globally in a short time in 2020. The COVID-19 was caused by the virus called SARS-CoV-2. Early diagnosis is very important to block the infection of the virus. Therefore, during these months scientists have developed dozens of methods to achieve rapid and sensitive detection of the virus. Nowadays some of these new methods have been applied for producing the commercial detection kit and help people against the disease worldwide. DNA-based biosensors are useful tools that have been widely applied in the detection of molecular biomarkers. The good stability, high specificity, and excellent biocompatibility make the DNA-based biosensors versatile in application both in vitro and in vivo. In this paper, we will review the major methods that emerged in recent years on the design of DNA-based biosensors and their applications. Moreover, we will also briefly discuss the possible future direction of DNA-based biosensors design. We believe this is helpful for people interested in not only the biosensor field but also in the field of analytical chemistry, DNA nanotechnology, biology, and disease diagnosis.

Keywords: DNA-Based biosensors; High performance; Molecular biomarkers.

Scheme 1

Basic concern of DNA-based biosensor. DNA is a material of target probe, signal transducer, and reporter carrier.

Fig. 1

Basic principle of the enzyme assisted DNA amplification reaction (A) loop-mediated isothermal amplification (LAMP) (B) rolling circle amplification (RCA) and (C) strand displacement amplification (SDA).

Fig. 2

Design of the DNA-based biosensors depended on enzyme-assisted DNA amplification processes. (A) The nicking-enzyme-dependent exponential RCA method. Reproduce from ref. (Huang et al., 2017) with permission from the Elsevier, copyright 2017 (B) High specific RNase HII assisted multiple amplification. Reproduce from ref. (Wang et al., 2018) with permission from the Royal Society of Chemistry, copyright 2018 (C) Cas12 related amplification system for detection of SARS-CoV-2. Reproduce from ref. (Broughton et al., 2020) with permission from the Nature Publishing Group, copyright 2020 (D) SDA-based multi-cycle amplification using the integrated probe. Reproduce from ref. (Cui et al., 2019b) with permission from the Royal Society of Chemistry, copyright 2019 (E) Design of the probe-amplifier-reporter trifunctional integrated platform (PARTIP). Reproduce from ref. (Cui et al., 2019a) with permission from the Royal Society of Chemistry, copyright 2019 (F) Nicking-enzyme assisted DNA nanowalker platform using target ssDNA as the fuel. Reproduce from ref. (Wang et al., 2017a) with permission from the American Chemical Society, copyright 2017.

Fig. 3

Basic principle of the enzyme-free DNA amplification reaction (A) hybridization chain reaction (HCR) (B) catalytic hairpins assembly (CHA) and (C) DNAzyme assisted amplification.

Fig. 4

Designs of the DNA-based biosensors dependent on the enzyme-free DNA amplification methods. (A) HCR between DNA tetrads based on the streptavidin-biotin scaffold. Reproduce from ref. (Huang et al., 2018a) with permission from the Royal Society of Chemistry, copyright 2018. (B) Localized CHA based on a DNA nanowire template. Reproduce from ref. (Wei et al., 2018) with permission from the Royal Society of Chemistry, copyright 2018. (C) Using qTDN structure to accelerate the efficiency of HCR. Reproduce from ref. (Wang et al., 2019c) with permission from the Royal Society of Chemistry, copyright 2019. (D) AuNP supported DNA nanowalker based on catalytic DNA cleavage of the DNAzyme. Reproduce from ref. (Peng et al., 2017) with permission from the Nature Publishing Group, copyright 2017.

Fig. 5

Designs of the DNA-based biosensors without the DNA amplification process. (A) The modified target nucleic acid strands can form a Y-shape structure with the probes anchored on the electrode for further electric signal transduce. Reproduce from ref. (Li et al., 2016) with permission from the American Chemical Society, copyright 2016. (B) Special DNA strands can form a G-quadruplex structure and bring the ferrocene molecules close to the electrode. Reproduce from ref. (Zhang et al., 2020b) with permission from the American Chemical Society, copyright 2020 (C) Allosteric regulation of a DNA triplex structure to control the release of the signal strand by the targeted antibody. Reproduce from ref. (Ranallo et al., 2017) with permission from the Nature Publishing Group, copyright 2017 (D) An ATP-responsive mitochondrial probe constructed based on hybridized PNA and DNA aptamer. Reproduce from ref. (Lin et al., 2020) with permission from the Royal Society of Chemistry, copyright 2020 (E) Using the DNA aptamers as the probe of SARS-COV-19 for detection of the virus by a lateral flow assay. Reproduce from ref. (Kacherovsky et al., 2021) with permission from the Wiley-VCH, copyright 2020.