Contents lists available at ScienceDirect Talanta journal homepage: www.elsevier.com/locate/talanta Biosensing strategies based on organic-scafolded metal nanoclusters for ultrasensitive detection of tumor markers Leila Farzin a,∗ , Mojtaba Shamsipur b , Leila Samandari b , Sodeh Sadjadi a , Shahab Sheibani a a Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, Iran b Department of Chemistry, Razi University, Kermanshah, Iran ARTICLEINFO Keywods: Biosensing strategies Cancer Nanocluster Scofold ABSTRACT The recent rapid advances in the synthesis, functionalization and application of nanomaterials have enabled scientists to develop metal nanoclusters (MNCs) stabilized with a variety of scafolds/protecting ligands in- cluding thiols, polymers, proteins, dendrimers and nucleic acids. Considering the unique optical, electronic and physical properties of MNCs, they have been successfully used for the tumor marker biosensing assays. In recent years, the ultrasensitive and accurate detection of tumor markers has been of critical importance for the screening or diagnosis of cancers at their early stages. Nanoclusters have revolutionized the design of biosensors and provided an opportunity for the selective and sensitive determination of tumor markers. Here, we review the synthesis, stabilization and promising applications of fuorescent MNCs, with particular focus on their potential for designing tumor marker biosensors. Finally, the current challenges and future perspectives on the emerging MNC-based biosensors are highlighted as well. Our intended audiences are the broader scientifc communities interested in the nanomaterial-based biosensors, and our review paper will, hopefully, open up new horizons for those scientists who manipulae the biological properties of nanoclusters. This review is based on publications available up to January 2020. 1. Introduction The integration of nanotechnology with biology, biochemistry and medicine is a very active feld of research. In particular, nano- technology holds enormous potentials for overcoming many of the problems associated with conventional methods in the detection and treatment of cancer. Since cancer is the second leading cause of death globally [1], screening and early diagnosis of this disease is a vital issue for the reduction of mortality rates of cancer patients. Currently, tumor markers are playing an increasingly important role in detection and management of cancer. Tumor markers are proteins synthesized by tumor cells or by sur- rounding tissues or cells as response to the tumor. However, non-can- cerous conditions may also cause elevation of some tumor markers to higher values than the normal level. There are a large number of tumor markers which are used for diferent types of cancers; many tumor markers may also be elevated in more than one type of cancer. A summary of the traditional tumor markers and their normal ranges in the human whole blood are given in Table 1. Thus, the ultrasensitive determination of tumor markers contributes to the detection and clin- ical treatment of some diseases, especially cancer. The traditionally used colorimetric immunoassays based on enzyme-linked im- munosorbent assays (ELISA) have opened opportunities for the de- termination of tumor markers, with excellent sensitivity, high specif- city and increased selectivity, due to occurrence of an antigen-antibody reaction. However, the antibody labeling, that is necessary for each ELISA, may result in inactivation of antibody. In addition, this proce- dure is time and cost consuming. To solve this problem, various bio- sensors have been designed to detedmine tumor markers. Despite recent advances in biosensing devices, their commercialization is still at an early beginning stage. Thus, there is a great need for compact, portable and point-of-care (POC) biosensors. The combination of biosensing methodologies with nanotechnology will provide the opportunities to facilitate the plan for commertialization of biosensors. Nanotechnology has revolutionized the happenings in the domain of biosensors [2] and consequently, has provided an opportunity for the determination of tumor markers. Nanotechnology has enabled the de- sign of in vitro sensing devices with high sensitivity, selectivity, and capability to carry out portable-based simultaneous measurements of multiple targets. This is due to the unique physicochemical and size- dependent properties of the nanomaterials. When the size of the na- nostructures is reduced to less than 10 nm, a quantum confnement https://doi.org/10.1016/j.talanta.2020.120886 Received 9 January 2020; Received in revised form 25 February 2020; Accepted 27 February 2020 ∗ Corresponding author. E-mail address: lfarzin@aeoi.org.ir (L. Farzin). Talanta 214 (2020) 120886 Available online 28 February 2020 0039-9140/ © 2020 Elsevier B.V. All rights reserved. T