Volume 5 Number 1 2026
Salivary exosomal mRNA and biosensors for the non-invasive detection of oral cancer
Yoghinni Manogaran 1* Shazmin Kithur Mohamed 2
Biosensors and Nanotheranostics 5 (1) 1-8 https://doi.org/10.25163/biosensors.5110996
Submitted: 03 September 2026 Revised: 20 October 2026 Accepted: 30 October 2026 Published: 01 November 2026
Oral squamous cell carcinoma (OSCC) accounts for roughly nine in every ten oral cancers, yet survival has barely moved in decades, mainly because most tumors are found late. Patients diagnosed at Stages I–II have five-year survival of 80%–90%, whereas those diagnosed at Stages III–IV fall to about 30%. Scalpel biopsy remains the diagnostic standard, but it is invasive, cannot be repeated freely, and depends on a lesion already being visible. Saliva offers a different starting point. It bathes the tumor directly, and the exosomes shed into it carry messenger RNA (mRNA) inside a lipid bilayer that protects it from salivary nucleases. In this review, we bring together the evidence on salivary exosomal mRNA as a biomarker class for OSCC and on biosensors that might read it at the point of care. A structured search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar informed a narrative synthesis covering exosome biology, isolation technologies, biomarker performance, and sensor engineering. In paired-sample data, nine salivary exosomal transcripts were all upregulated, and a TNF-α/OAZ1 panel reached an area under the curve of 0.89 (80% sensitivity, 90% specificity). Salivary MMP-9 and OAZ1 tracked tumor grade, and IL-6 tracked nodal metastasis; serum markers did neither. Electrochemical, SERS, microfluidic, CRISPR-based, and electric field-induced platforms report attomolar-to-femtomolar detection limits in microlitre volumes, although most have not yet targeted mRNA in OSCC saliva. Single-cohort evidence, pre-analytical variability, and vesicle heterogeneity remain the main barriers. We close by outlining the validation and standardization steps needed before such devices can reach routine clinics.
Keywords: oral squamous cell carcinoma; saliva; exosomes; extracellular vesicles; messenger RNA; liquid biopsy; biosensor; point-of-care diagnostics; early detection
Asakura, K., Kadota, T., Matsuzaki, J., Yoshida, Y., Yamamoto, Y., Nakagawa, K., Takizawa, S., Aoki, Y., Nakamura, E., Miura, J., Sakamoto, H., Ochiya, T., & Sanada, M. (2020). A large-scale validation study of a diagnostic model based on serum microRNA expression profiles for lung cancer. Cancer Science, 111(9), 3326-3336.
Babiuch, K., Bednarczyk, A., Gawron, K., Krzysciak, P., Budzynska, A., & Chomyszyn-Gajewska, M. (2020). Evaluation of proinflammatory, NF-kappaB dependent cytokines: IL-1α, IL-6, IL-8, and TNF-α in tissue specimens and saliva of patients with oral squamous cell carcinoma and oral potentially malignant disorders. Journal of Clinical Medicine, 9(3), Article 856. https://doi.org/10.3390/jcm9030867
Cancers Editorial Office. (2024). Advances in saliva diagnostics and exosome analysis for non-invasive cancer detection. Cancers, 16(18), Article 3298.
Carrell, C., Kava, A., Nguyen, M., Menger, R., Munshi, Z., Call, Z., & Henry, C. S. (2019). Beyond the lateral flow assay: A review of paper-based microfluidics. Microelectronic Engineering, 206, 45-54.
https://doi.org/10.1016/j.mee.2018.12.002
Chandrasekaran, Y., Kayal, L., Babu, N. A., Jothinathan, M. K., & Behera, A. (2024). Salivary biomarkers: A promising avenue for advancing oral cancer detection. Oral Oncology Reports, 1, Article 100315.
https://doi.org/10.1016/j.oor.2024.100315
Dong, T., & Pires, N. M. M. (2017). Immunodetection of salivary biomarkers by an optical microfluidic biosensor with polyethylenimine-modified polythiophene-C70 organic photodetectors. Biosensors and Bioelectronics, 94, 321-327.
https://doi.org/10.1016/j.bios.2017.03.005
Faur, C. I., Dinu, C., Toma, V., Jurj, A., Marginean, R., Onaciu, A., Moldovan, C. S., Cri?an, B., Baciut, M., Baciut, G., & Berindan-Neagoe, I. (2023). A new detection method of oral and oropharyngeal squamous cell carcinoma based on multivariate analysis of surface enhanced Raman spectra of salivary exosomes. Journal of Personalized Medicine, 13(5), Article 762.
https://doi.org/10.3390/jpm13050762
Fehlmann, T., Kahraman, M., Ludwig, N., Backes, C., Galata, V., Keller, V., Geffers, L., Mergenthaler, P., Jost, N. J., & Keller, A. (2020). Evaluating the use of circulating microRNA profiles for lung cancer detection in symptomatic patients. JAMA Oncology, 6(5), 714-723. https://doi.org/10.1001/jamaoncol.2020.0001
Gau, V., & Wong, D. (2007). Oral fluid nanosensor test (OFNASET) with advanced electrochemical-based molecular analysis platform. Annals of the New York Academy of Sciences, 1098, 401-410.
https://doi.org/10.1196/annals.1384.005
Hong, J. S., Son, T., Castro, C. M., & Im, H. (2023). CRISPR/Cas13a-based microRNA detection in tumor-derived extracellular vesicles. Advanced Science, 10(18), Article e2301766.
https://doi.org/10.1002/advs.202301766
Kang, Y., Ding, Y., Chen, Z., & Wang, Y. (2022). Evaluation of serum exosomal circRNAs as novel diagnostic biomarkers for lung adenocarcinoma. Respiratory Research, 23(1), Article 183.
Kashefi-Kheyrabadi, L., Nguyen, H. V., Go, A., Baek, C., Jang, N., Ghahremanloo, M., & Kim, M. I. (2020). Ultrasensitive electrochemical detection of cancer-derived exosomes using an aptamer-based biosensor. Biosensors and Bioelectronics, 150, Article 111863.
Kumar, S. K., Kanaparthi, N., Annes, S. B., Bendre, R. V., Balakrishna, N., Kumar, S., Hakeem, A. H., & Sasidhar, M. V. (2025). Evaluation of salivary and serum exosomal mRNAs as biomarkers for the diagnosis and prognosis of oral squamous cell carcinoma. Scientific Reports, 15(1), Article 22246.
https://doi.org/10.1038/s41598-025-22246-1
Lee, J. M., Garon, E., & Wong, D. T. (2009). Salivary diagnostics. Orthodontics & Craniofacial Research, 12(3), 206-211.
https://doi.org/10.1111/j.1601-6343.2009.01454.x
Li, S., Zhang, M., Zhang, H., & Wang, X. (2020). Exosomal long noncoding RNA lnc-GNAQ-6:1 may serve as a diagnostic marker for gastric cancer. Clinica Chimica Acta, 501, 252-257.
https://doi.org/10.1016/j.cca.2019.10.047
Li, T., Li, J., Wang, H., Zhao, J., Yan, M., He, H., & Yu, S. (2022). Exosomes: Potential biomarkers and functions in head and neck squamous cell carcinoma. Frontiers in Molecular Biosciences, 9, Article 881794.
https://doi.org/10.3389/fmolb.2022.1056179
Lisa Cheng, Y. S., Jordan, L., Rees, T., Chen, H. S., & Oxford, L. (2014). Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. Journal of Periodontology, 85(7), 956-965.
https://doi.org/10.1902/jop.2013.130320
Nonaka, T., & Wong, D. T. W. (2022). Liquid biopsy in head and neck cancer: Promises and challenges. Non-Coding RNA, 8(5), Article 60.
Osteikoetxea, X., Balogh, A., Szabó-Taylor, K., Németh, A., Szabó, T. G., Pálóczi, K., Sódar, B., Kittel, Á., György, B., Pállinger, É., & Buzás, E. I. (2015). Improved characterization of EV preparations based on protein to lipid ratio and lipid properties. PLoS ONE, 10(3), Article e0121184. https://doi.org/10.1371/journal.pone.0121184
Pan, B., Qin, J., Liu, X. X., & Xu, T. (2019). Identification of serum exosomal hsa-circ-0004771 as a novel diagnostic biomarker of colorectal cancer. Frontiers in Genetics, 10, Article 10.
https://doi.org/10.3389/fgene.2019.01096
Pan, S., & Zhang, C. (2026). Extracellular vesicles as regulators of chemotherapy resistance in oral squamous cell carcinoma. Discover Oncology, 17(1), Article 5096. https://doi.org/10.1007/s12672-026-05096-9
https://doi.org/10.1007/s12672-026-05096-9
Roy, S., Kanda, M., Nomura, S., Zhu, Z., Toiyama, Y., Taketomi, A., & Kodera, Y. (2022). Diagnostic efficacy of circular RNAs as noninvasive, liquid biopsy biomarkers for early detection of gastric cancer. Molecular Cancer, 21(1), Article 42.
https://doi.org/10.1186/s12943-022-01527-7
Sackmann, E. K., Fulton, A. L., & Beebe, D. J. (2014). The present and future role of microfluidics in biomedical research. Nature, 507(7491), 181-189. https://doi.org/10.1038/nature13118
Senevirathna, K., Jayasinghe, R. D., & Amarasinghe, H. (2024). Diagnostic potential of salivary IL-1β, IL-8, SAT, S100P, and OAZ1 in oral squamous cell carcinoma, oral submucous fibrosis, and oral lichen planus based on findings from a Sri Lankan cohort. Scientific Reports, 14(1), Article 27226.
https://doi.org/10.1038/s41598-024-75735-0
Shin, H., Choi, B. H., Shim, O., Kim, J., Park, Y., Cho, S. K., Kim, H. K., & Choi, Y. (2023). Single test-based diagnosis of multiple cancer types using exosome-SERS-AI for early stage cancers. Nature Communications, 14(1), Article 1644.
https://doi.org/10.1038/s41467-023-37403-1
Song, E., & Yang, D. (2026). Emerging non-invasive diagnostic approaches for early detection of oral squamous cell carcinoma. Cancer Management and Research, 18, 1-18. https://doi.org/10.2147/CMAR.S569352
https://doi.org/10.2147/CMAR.S569352
Tang, H., Yu, D., Zhang, J., Wang, M., Fu, M., Qian, Y., Zhang, X., Ji, R., Gu, J., & Zhang, X. (2024). The new advance of exosome-based liquid biopsy for cancer diagnosis. Journal of Nanobiotechnology, 22(1), Article 610. https://doi.org/10.1186/s12951-024-02863-0
Ten, A., Kumeiko, V., Farniev, V., Gao, H., & Shevtsov, M. (2024). Tumor microenvironment modulation by cancer-derived extracellular vesicles. Cells, 13(8), Article 682. https://doi.org/10.3390/cells13080682
Tu, M., Cheng, J., Chen, Y. L., Jea, W. C., Chen, W. L., Chen, C. J., & Wong, D. T. (2020). Electric field-induced release and measurement (EFIRM): Characterization and technical validation of a novel liquid biopsy platform in plasma and saliva. The Journal of Molecular Diagnostics, 22(8), 1050-1062. https://doi.org/10.1016/j.jmoldx.2020.05.005
Wang, M., Pan, Y., Wu, S., Sun, Z., Wang, L., Yang, J., Yin, Y., & Li, G. (2020). Detection of colorectal cancer-derived exosomes based on covalent organic frameworks. Biosensors and Bioelectronics, 169, Article 112638.
https://doi.org/10.1016/j.bios.2020.112638
Wei, F., Lin, C. C., Joon, A., Feng, Z., Troche, G., Lira, M. E., Chia, D., Mao, M., Tu, M., & Wong, D. T. (2014). Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer. American Journal of Respiratory and Critical Care Medicine, 190(10), 1117-1126. https://doi.org/10.1164/rccm.201406-1003OC
Wei, F., Yang, J., & Wong, D. T. (2013). Detection of exosomal biomarker by electric field-induced release and measurement (EFIRM). Biosensors and Bioelectronics, 44, 115-121.
https://doi.org/10.1016/j.bios.2012.12.046
Welsh, J. A., Goberdhan, D. C. I., O'Driscoll, L., Buzas, E. I., Blenkiron, C., Bussolati, B., Cai, H., Di Vizio, D., Driedonks, T. A. P., Erdbrügger, U., Falcon-Perez, J. M., Fu, Q. L., Hill, A. F., Lenassi, M., Lötvall, J., Nieuwland, R., Ochiya, T., Romanov, S., Sahoo, S., . . . Witwer, K. W. (2024). Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of Extracellular Vesicles, 13(2), Article e12404.
https://doi.org/10.1002/jev2.12404
Wu, M., Chen, Z., Xie, Q., Xiao, B., Zhou, G., Chen, G., & Bian, Z. (2021). One-step quantification of salivary exosomes based on combined aptamer recognition and quantum dot signal amplification. Biosensors and Bioelectronics, 171, Article 112733. https://doi.org/10.1016/j.bios.2020.112733
Xu, J., Zhang, L., & Wang, Y. (2024). Saliva-derived exosomes: Biological roles and clinical applications in salivary gland tumors and oral cancers. Cancers, 16(19), Article 3298. https://doi.org/10.3390/cancers16193298
https://doi.org/10.3390/cancers16193298
Yuan, G., Xie, H., Wei, T., Zhu, D., Zhang, C., & Yang, Y. (2021). Diagnostic potential of extracellular vesicle-associated microRNA-10b and tumor markers for lung adenocarcinoma. Oncology Letters, 22(2), Article 614.
https://doi.org/10.3892/ol.2021.12875
Zeng, D., Wang, Z., Meng, Z., Muranko, J. E., & Xia, J. (2017). DNA tetrahedral nanostructure-based electrochemical miRNA biosensor for simultaneous detection of multiple miRNAs in pancreatic carcinoma. ACS Applied Materials & Interfaces, 9(28), 24118-24125. https://doi.org/10.1021/acsami.7b05981
Zhang, H., Wang, Z., & Liu, Y. (2025). Emerging electrochemical biosensors and nanomaterials for extracellular vesicle detection. Molecules, 30(5), Article 2708. https://doi.org/10.3390/molecules30132708
Zhong, G. B., Wang, K. Q., Li, J. W., & Zhang, J. (2020). Determination of serum exosomal H19 as a noninvasive biomarker for breast cancer diagnosis. OncoTargets and Therapy, 13, 2563-2571. https://doi.org/10.2147/OTT.S243601
Zlotogorski-Hurvitz, A., Dekel, B. Z., Malonek, D., Yahalom, R., & Vered, M. (2019). FTIR-based spectrum of salivary exosomes coupled with computational-aided discriminating analysis in the diagnosis of oral cancer. Journal of Cancer Research and Clinical Oncology, 145(3), 685-694. https://doi.org/10.1007/s00432-018-02827-6
Engineered Extracellular Vesicles Escape Endosomal Trapping to Deliver Alzheimer's Therapeutics Across the Blood-Brain Barrier
Computational Design of Protein-Based Diagnostic Assays for Early Cancer Detection: Platforms, Algorithms, and the Road to Clinical Translation
Engineering the Lipid Nanoparticle Through Formulation Chemistry, Analytical Characterization, and Machine-Learning-Guided Optimization of mRNA Vaccine Delivery Systems