Talanta 227 (2021) 122188 Available online 6 February 2021 0039-9140/© 2021 Elsevier B.V. All rights reserved. Review A review of aptamer-based SERS biosensors: Design strategies and applications Muhammad Muhammad a, b , Qing Huang a, b, * a CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China b Science Island Branch of Graduate School, University of Science and Technology of China, China A R T I C L E INFO Keywords: Surface-enhanced Raman spectroscopy (SERS) Aptamers Nanoparticles (NPs) Nanostructure Biosensors ABSTRACT Surface-enhanced Raman spectroscopy, due to its high sensitivity, unique vibrational fngerprint identifcation of molecules and easy operation, has been extensively applied in different felds. Aptamers, being the unique single stranded DNA/RNA sequences that can specifcally recognize and seize the target analytes, combined with Surface-enhanced Raman spectroscopy (SERS), can offer potent multiplex detection capacity with high speci- fcity and sensitivity. In this review, we summarize and classify the general working strategies of different types of aptamer-based SERS biosensors with diversifed protocols which either take aptamer conformational change as intrinsic reporter, or make use of various extrinsic Raman reporters in different sensor designs via on/off approach, sandwich-type and magnetic nanoparticles (NPs)-assisted approach, and catalytic reaction assisted approach with amplifcation of alternative Raman signals. The advantages, applications and perspectives of these aptamer-based SERS biosensors are also discussed. 1. Introduction Aptamers are single-stranded DNA/RNA sequences owing to unique binding features to their targets, and they have been widely applied in diverse felds of research [1–7]. They are short nucleotide sequences with the molecular weight ranging from 10 to 30 kDa, much smaller than that of antibodies [8,9]. Compared to RNA, DNA strands are more stable in vitro and easier to acquire through different selection proced- ures [10]. Normally, they can be identifed and isolated from large li- brary of oligonucleotide sequences through multiple rounds of selection procedure well-known as SELEX, which stands for “Systematic Evolution of Ligands by Exponential Enrichment” [11,12]. With the distinct three dimensional (3D) conformational change upon binding with the target molecules, aptamers can catch the targets by forces such as hydrogen bonding, van der Waals force, and the force due to stacking of aromatic rings and salt bridging [13]. Generally, aptamers have the advantages such as high affnity and specifcity, as well as the readiness for modi- fcation with functional molecules [14,15]. In comparison with anti- bodies, they are stable at room temperature, nearly 10-folds small in size, and easier to acquire based on the SELEX technique. The dissoci- ation constant for target protein binding can be furthered improved in aptamers with the use of thymine string [16]. Because aptamers are relatively cheap in production and can be synthesized quickly, nowa- days they have been used in wide range of applications such as biomedical diagnosis, bio-imaging, and therapeutics [10,17]. In recent years, outstanding with the sensitivity and unique molec- ular spectral resolution [18], SERS has gained increasing attention for the analyses of biological molecules [19–23], water pollutants [24,25], food processing [26–29], antibiotic response [30–32] etc. SERS is the enhancement of Raman signals of adsorbed molecules on the SERS substrate surface. This phenomena, however, can be explained by two widely accepted yet different factors, i.e., the electromagnetic enhancement factor and the chemical enhancement factor [33,34]. The electromagnetic enhancement is largely based on electric feld magni- fcation due to exited localized surface plasmon resonance, while the chemical enhancement occurs because of the creation of charge transfer states between the SERS substrate and the chemisorbed molecules [34]. Thus, fabrication of such substrates or platforms is critical, and currently it is still a major challenge to provide specifc and sensitive enhancement of Raman signals in complex biological environment. Due to the specifc interaction of aptamers with target molecules, aptamer-based SERS assays have effectively revamped the matrix of * Corresponding author. CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. E-mail address: huangq@ipp.ac.cn (Q. Huang). Contents lists available at ScienceDirect Talanta journal homepage: www.elsevier.com/locate/talanta https://doi.org/10.1016/j.talanta.2021.122188 Received 5 December 2020; Received in revised form 27 January 2021; Accepted 30 January 2021