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Lin, B.;  Jiang, J.;  Jia, J.;  Zhou, X. Exosomal miRNA Biosensing for Liquid Biospy. Encyclopedia. Available online: (accessed on 19 June 2024).
Lin B,  Jiang J,  Jia J,  Zhou X. Exosomal miRNA Biosensing for Liquid Biospy. Encyclopedia. Available at: Accessed June 19, 2024.
Lin, Bingqian, Jinting Jiang, Jingxuan Jia, Xiang Zhou. "Exosomal miRNA Biosensing for Liquid Biospy" Encyclopedia, (accessed June 19, 2024).
Lin, B.,  Jiang, J.,  Jia, J., & Zhou, X. (2022, November 09). Exosomal miRNA Biosensing for Liquid Biospy. In Encyclopedia.
Lin, Bingqian, et al. "Exosomal miRNA Biosensing for Liquid Biospy." Encyclopedia. Web. 09 November, 2022.
Exosomal miRNA Biosensing for Liquid Biospy

As a noninvasive detection technique, liquid biopsy plays a valuable role in cancer diagnosis, disease monitoring, and prognostic assessment. In liquid biopsies, exosomes are considered among the potential biomarkers because they are important bioinformation carriers for intercellular communication. Exosomes transport miRNAs and, thus, play an important role in the regulation of cell growth and function; therefore, detection of cancer cell-derived exosomal miRNAs (exo-miRNAs) gives effective information in liquid biopsy. 

exosomal miRNA biosensing liquid biopsy

1. Introduction

Cancer is one of the major diseases that threaten human health today, and its incidence and mortality rates are on a continuous rise [1]. Clinical research and practices have shown that the development of precision diagnosis and treatment technologies to achieve early diagnosis and early treatment of tumors is an important strategy to reduce the mortality rate and improve the survival rate of cancer patients [2]. As the gold standard technology for tumor diagnosis, tissue biopsy can obtain pathological information of tumors, including molecular biological characteristics, which provides important reference values for tumor diagnosis, as well as treatment [3]. However, traditional tissue biopsy techniques require invasive sampling procedures or even surgical assistance, and they have limitations such as large sampling bias, difficulty in sampling due to deteriorating clinical conditions or deep tumor location, and sampling lag [4]. Therefore, it is of great significance to explore noninvasive strategies for accurate early tumor diagnosis and monitor. Unlike noninvasive imaging for cancer monitoring [5][6], liquid biopsy is a technique that detects, analyzes, and monitors tumors by analyzing various body fluid samples such as blood or urine [7]. Compared with traditional tissue biopsy techniques that are limited to tumor progression at a single timepoint and suffer from bias due to tumor heterogeneity, liquid biopsy is one of the frontier hotspots in tumor diagnosis because it is less invasive, is convenient for multiple sampling, and can monitor tumor progression in real time.
At present, the main targets of liquid biopsy include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles, such as exosomes [8]. Among these, exosomes derived from cancer cells may serve as a promising biomarker for several cancers [9]. Exosomes, a type of extracellular vesicle (EV), 40-160 nm in size, are secreted by all eukaryotic cells [10]. They have stable structures consisting of bilateral phospholipid membranes with proteins, DNA, mRNAs, microRNAs (miRNAs), etc. inside. These cargoes are proven to play a vital role in cell-to-cell communication [11]. Special markers associated with tumor-derived exosomes may be enriched, which may be useful for diagnosis. In particular, unique nucleic acids contained in exosomes are potentially reliable biomarkers in the diagnosis and progress monitoring of cancer. MicroRNAs are a major class of single-stranded, noncoding RNA with a length of 19-25 nucleotides (nts), which are essential regulators of gene expression, especially in cancer [12]. Recent studies have identified miRNAs in exosomes as potential biomarkers for liquid biopsy and are expected to be used in future clinical tests.

2. The Potential of Exo-miRNAs as Biomarkers in Liquid Biopsy

2.1. MicroRNAs as a Biomarker

Growing evidence has shown that miRNAs play an important role in the process of cancer development, including tumorigenesis, metastasis, and treatment resistance [13]. In most cases, miRNAs bind to their complementary sequences in the 3′ untranslated region (UTR) of target mRNAs to modulate their target [12]. In addition to the predominant mechanism, other non-canonical mechanisms have been demonstrated. Massive research has revealed that miRNAs are greatly involved in human health by regulating more than 60% of protein-coding genes and account for about 1% of the genome [14]. Additionally, the altered expression levels of miRNAs are associated with chromosomal abnormalities in their parent cells. Since then, a large number of studies have made efforts to investigate the noncoding transcriptomes from various cancer types, trying to provide appropriate miRNA candidates as a biomarker in liquid biopsy [15]. Comprehensive studies of the dysregulated profile of miRNAs in circulating environments such as blood have shown that they are associated with cancer [16]. Thus, altered levels of relevant miRNAs in liquid biopsy may provide rich information in cancer diagnosis.

2.2. Exo-miRNAs as Biomarker in Liquid Biopsy

In general, the release of miRNAs circulating in the body fluids follows two paths. The passive path mainly relies on tissue damage, apoptosis, and necrotic cell death. On the other hand, cells can actively encapsulate miRNAs in extracellular vesicles, such as exosomes and ectosomes. It has been shown that about 10% of secretory miRNAs are enriched in exosomes, while the remaining are associated with proteins in the circulation [17][18]. Taking advantage of the membrane structure, the miRNAs show improved stability against the degradation of RNases. Moreover, the intact structure of exosomes is not affected by non-physiological conditions, such as repeated freezing and thawing, extreme pH, or long-term storage, thus allowing the internal miRNAs to remain stable, laying the foundation for the sensitivity of miRNA detection [19].
Recent studies have demonstrated that exosomes derived from cancer cells are ideal candidate biomarkers for early cancer diagnosis and therapeutic monitoring. It has been reported that miRNAs are involved in the pathogenesis of various diseases, including cancer, through the exosomes that are taken up by the recipient cells as cargo [20][21]. Increasing evidence has revealed that miRNAs transferred by exosomes contain valuable information about the original cell types, the recipient cells, and disease progression. It has been reported that the exo-miRNAs derived from cancer cells can promote cell proliferation, migration, and angiogenesis [19], such as exosomal-miR-21 (exo-miR-21) [22], exo-miR-23a [23], exo-miR-100 [24], and so on [25][26]. For instance, exo-miR-21 was investigated as a promising biomarker for breast cancer [27] and ovarian cancer [28]. So far, 2838 miRNAs have been reported to be encapsulated in exosomes from several kinds of cell types (Exocarta) [29]. Therefore, it is of great significance to use exo-miRNAs as a detection target in liquid biopsy for early diagnosis, progression monitoring, and therapy evaluation of cancer.
Several methods for exo-miRNAs analysis have been reported. The common methods used to quantitative and profile miRNAs are quantitative reverse transcription real-time PCR (qRT-PCR) [22], digital PCR [30], and next-generation sequencing (NGS) [31]. However, despite the superior performance of these methods, they have some shortcomings in the application of liquid biopsy. Quantitative real-time PCR (qRT-PCR) has been recognized as the gold standard for miRNA analysis due to its excellent sensitivity and flexibility. However, this method has some problems such as non-absolute quantification, false positives, reliance on expensive equipment, and a large number of biological samples, which limit its application in routine clinical practice [30]. In addition, the ddPCR and NGS usually need high costs and tedious operations, limiting the use of these assays in a large number of clinical liquid biopsy scenarios [32]. Many biosensors are designed to explore disease-associated markers, such as detecting cancer-associated markers for cancer diagnosis [33][34][35]. Compared with the above methods, miRNA detection using biosensors does not require complex steps with shortened detection time and does not require large and expensive instruments, meeting the requirements of rapid and high sensitivity for clinical detection in liquid biopsy.


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