materials Review Recent Advancements in Nanoparticle-Based Optical Biosensors for Circulating Cancer Biomarkers Chaima Amri 1 , Arvind Kumar Shukla 2 and Jin-Ho Lee 1,2, *   Citation: Amri, C.; Shukla, A.K.; Lee, J.-H. Recent Advancements in Nanoparticle-Based Optical Biosensors for Circulating Cancer Biomarkers. Materials 2021, 14, 1339. https://doi.org/10.3390/ ma14061339 Academic Editor: Daniela Iannazzo Received: 19 February 2021 Accepted: 8 March 2021 Published: 10 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Convergence Medical Sciences, School of Medicine, Pusan National University, Yangsan 50612, Korea; a.chaima@pusan.ac.kr 2 School of Biomedical Convergence Engineering, Pusan National University, Yangsan 50612, Korea; arvindkumarshukla@pusan.ac.kr * Correspondence: leejh@pusan.ac.kr; Tel.: +82-51-510-8547 Abstract: The effectiveness of cancer treatment strongly depends on the early detection of the disease. Currently, the most common diagnostic method, tissue biopsy, takes time and can be damaging to the patient. Circulating cancer biomarkers such as circulating tumor DNA, micro-RNA (miRNA), tumor proteins, exosomes, and circulating tumor cells have repeatedly demonstrated their viability as targets for minimally invasive cancer detection through liquid biopsies. However, among other things, achieving a great sensitivity of detection is still challenging due to the very low concentration of biomarkers in fluid samples. This review will discuss how the recent advances in nanoparticle- based biosensors are overcoming these practical difficulties. This report will be focusing mainly on optical transduction mechanisms of metal nanoparticles (M-NPs), quantum dots (QDs), and upconversion nanoparticles (UCNPs). Keywords: optical biosensors; circulating cancer biomarkers; optical transduction; metal nanoparti- cles (M-NPs); quantum dots (QDs); upconversion nanoparticles (UCNPs) 1. Introduction The early detection of cancer considerably impacts the effectiveness of oncotherapy. Currently, tissue biopsies are commonly used as an affordable and accurate diagnostic method. However, on top of being a time-consuming procedure, tissue biopsies can be difficult to reproduce. In certain cases, tissue sampling can require a more invasive procedure that can be frightening or even damaging to the patient. Thus, it is important to develop faster, less invasive, and more precise biosensors. Recently, the sensing of circulating cancer biomarkers such as circulating tumor DNA (ctDNA), circulating micro- RNA (miRNA), tumor proteins, exosomes, or even circulating tumor cells (CTCs) have been gaining a lot of attention as they allow for minimally invasive detection methods. However, the low concentration of those biomarkers renders most standard biosensors obsolete. Circulating cancer biomarkers are molecules of different forms mostly present in body fluids such as the serum/plasma, saliva, or urine of cancer patients. Among those biomarkers, ctDNAs are short fragments of cell-free DNA originating from tumor cells [1]. The release mechanism of ctDNAs is not clearly understood yet, but recent studies have demonstrated a positive correlation between ctDNA levels and tumor burden in animal models [2]. On the other hand, circulating miRNA, stable non-coding small RNAs, are differentially expressed depending on the stage of tumor progression [3]. Currently, most ctDNA and miRNA analyses are performed in liquid biopsies through variations of poly- merase chain reaction (PCR), microarray, or next-generation sequencing with each certain disadvantages: a small number of target genes, a low throughput, or the cost of the equip- ment [2,4–7]. Furthermore, serum proteins have been successfully targeted in the detection of various types of cancers such as breast cancer [8] and epithelial ovarian cancer [9], as Materials 2021, 14, 1339. https://doi.org/10.3390/ma14061339 https://www.mdpi.com/journal/materials