Emerging roles of exosomes in oral diseases progression

Abstract

Oral diseases, such as periodontitis, salivary gland diseases, and oral cancers, significantly challenge health conditions due to their detrimental effects on patient’s digestive functions, pronunciation, and esthetic demands. Delayed diagnosis and non-targeted treatment profoundly influence patients’ prognosis and quality of life. The exploration of innovative approaches for early detection and precise treatment represents a promising frontier in oral medicine. Exosomes, which are characterized as nanometer-sized extracellular vesicles, are secreted by virtually all types of cells. As the research continues, the complex roles of these intracellular-derived extracellular vesicles in biological processes have gradually unfolded. Exosomes have attracted attention as valuable diagnostic and therapeutic tools for their ability to transfer abundant biological cargos and their intricate involvement in multiple cellular functions. In this review, we provide an overview of the recent applications of exosomes within the field of oral diseases, focusing on inflammation-related bone diseases and oral squamous cell carcinomas. We characterize the exosome alterations and demonstrate their potential applications as biomarkers for early diagnosis, highlighting their roles as indicators in multiple oral diseases. We also summarize the promising applications of exosomes in targeted therapy and proposed future directions for the use of exosomes in clinical treatment.

References

1. Le, H.et al.Oral health disparities and inequities in Asian Americans and Pacific Islanders.Am. J. Public Health 107, S34-S35 (2017).
2. Peres, M. A.et al.Oral diseases: a global public health challenge.Lancet 394, 249-260 (2019).
3. Cheng L.& Hill, A. F. Therapeutically harnessing extracellular vesicles.Nat. Rev. Drug Discov. 21, 379-399 (2022).
4. Cocucci E.& Meldolesi, J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles.Trends Cell Biol. 25, 364-372 (2015).
5. Kalluri R.& LeBleu, V. S. The biology, function, and biomedical applications of exosomes.Science 367, eaau6977 (2020).
6. Meldolesi J.Exosomes and ectosomes in intercellular communication.Curr. Biol. 28, R435-R444 (2018).
7. Mathieu M.,Martin-Jaular, L., Lavieu, G. & Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication.Nat. Cell Biol. 21, 9-17 (2019).
8. Hessvik N. P.& Llorente, A. Current knowledge on exosome biogenesis and release.Cell. Mol. Life Sci. 75, 193-208 (2018).
9. van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles.Nat. Rev. Mol. Cell Biol. 19, 213-228 (2018).
10. Meyle J.& Chapple, I. Molecular aspects of the pathogenesis of periodontitis.Periodontol 2000 69, 7-17 (2015).
11. Kinane, D. F., Stathopoulou, P. G.& Papapanou, P. N. Periodontal diseases.Nat. Rev. Dis. Prim. 3, 17038(2017).
12. Cai, R.et al.The role of extracellular vesicles in periodontitis: pathogenesis, diagnosis, and therapy.Front. Immunol. 14, 1151322(2023).
13. Zhang, Z.et al.PDLSCs regulate angiogenesis of periodontal ligaments via VEGF transferred by exosomes in periodontitis.Int. J. Med. Sci. 17, 558-567 (2020).
14. Xia, Y.et al.The miR-223-3p regulates pyroptosis through NLRP3-Caspase 1-GSDMD signal axis in periodontitis.Inflammation 44, 2531-2542 (2021).
15. Chen, Z.et al.Oxidative stress state inhibits exosome secretion of hPDLCs through a specific mechanism mediated by PRMT1.J. Periodontal. Res. 57, 1101-1115 (2022).
16. Choi J.-W., Kim S.-C., Hong S.-H.& Lee, H.-J. Secretable small RNAs via outer membrane vesicles in periodontal pathogens.J. Dent. Res. 96, 458-466 (2017).
17. Elsayed, R.et al.Microbially-induced exosomes from dendritic cells promote paracrine immune senescence: novel mechanism of bone degenerative disease in mice.Aging Dis. 14, 136-151 (2023).
18. Liu, X.et al.Mechanisms of mechanical force aggravating periodontitis: a review. Oral Dis. https://doi.org/10.1111/odi.14566(2023).
19. Wu, Y.et al.Exosomes from cyclic stretched periodontal ligament cells induced periodontal inflammation through miR-9-5p/SIRT1/NF-κB signaling pathway. J. Immunol. https://doi.org/10.4049/jimmunol.2300074(2023).
20. Zhao M., Ma Q., Zhao Z., Guan X.& Bai, Y. Periodontal ligament fibroblast-derived exosomes induced by compressive force promote macrophage M1 polarization via Yes-associated protein.Arch. Oral. Biol. 132, 105263(2021).
21. Piccolo, S., Dupont, S.& Cordenonsi, M. The biology of YAP/TAZ: hippo signaling and beyond.Physiol. Rev. 94, 1287-1312 (2014).
22. Matthaios D., Tolia M., Mauri D., Kamposioras K.& Karamouzis, M. YAP/Hippo pathway and cancer immunity: it takes two to tango.Biomedicines 9, 1949(2021).
23. Atsawasuwan, P.et al.Secretory microRNA-29 expression in gingival crevicular fluid during orthodontic tooth movement.PLoS One 13, e0194238(2018).
24. Zheng, X.et al. Biological characteristics of microRNAs secreted by exosomes of periodontal ligament stem cells due to mechanical force. Eur. J. Orthod. https://doi.org/10.1093/ejo/cjad002 (2023).
25. Chang M., Chen Q., Wang B., Zhang Z.& Han, G. Exosomes from tension force-applied periodontal ligament cells promote mesenchymal stem cell recruitment by altering microRNA profiles.Int. J. Stem Cells 16, 202-214 (2023).
26. Huang, H.-M.et al.Mechanical force-promoted osteoclastic differentiation via periodontal ligament stem cell exosomal protein ANXA3.Stem Cell Rep. 17, 1842-1858 (2022).
27. Liu, X., Muhammed, F. K.& Liu, Y. Simvastatin encapsulated in exosomes can enhance its inhibition of relapse after orthodontic tooth movement.Am. J. Orthod. Dentofac. Orthop. 162, 881-889 (2022).
28. Sarode, G.et al.Epidemiologic aspects of oral cancer.Dis. Mon. 66, 100988(2020).
29. Hernández-Morales, A. et al. Lip and oral cavity cancer incidence and mortality rates associated with smoking and chewing tobacco use and the human development index in 172 countries worldwide: an ecological study 2019-2020.Healthcare 11, 1063(2023).
30. Tan, Y.et al.Oral squamous cell carcinomas: state of the field and emerging directions.Int. J. Oral. Sci. 15, 44(2023).
31. Qadir, F.et al.Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation.Mol. Cancer 17, 97(2018).
32. Razzo, B. M.et al.Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.Carcinogenesis 41, 625-633 (2020).
33. Li, X., Yang, T.& Shu, C. The oral tumor cell exosome miR-10b stimulates cell invasion and relocation via AKT signaling.Contrast Media Mol. Imaging 2022, 3188992(2022).
34. Li, C.et al.Exosomal long noncoding RNAs MAGI2-AS3 and CCDC144NL-AS1 in oral squamous cell carcinoma development via the PI3K-AKT-mTOR signaling pathway.Pathol. Res. Pract. 240, 154219(2022).
35. Hanahan D.Hallmarks of cancer: new dimensions.Cancer Discov. 12, 31-46 (2022).
36. Squarize, C. H.et al.PTEN deficiency contributes to the development and progression of head and neck cancer.Neoplasia 15, 461-471 (2013).
37. Yan, W.et al.Exosomal miR-130b-3p promotes progression and tubular formation through targeting PTEN in oral squamous cell carcinoma.Front. Cell Dev. Biol. 9, 616306(2021).
38. Hou, C.-X.et al.Exosomal microRNA-23b-3p promotes tumor angiogenesis and metastasis by targeting PTEN in salivary adenoid cystic carcinoma.Carcinogenesis 43, 682-692 (2022).
39. He, S.et al.Oral squamous cell carcinoma (OSCC)-derived exosomal MiR-221 targets and regulates phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) to promote human umbilical vein endothelial cells migration and tube formation.Bioengineered 12, 2164-2174 (2021).
40. Wang, H.et al.OSCC exosomes regulate miR-210-3p targeting EFNA3 to promote oral cancer angiogenesis through the PI3K/AKT pathway.BioMed. Res. Int. 2020, e2125656(2020).
41. Li, S.et al.Mesenchymal stem cell-exosome-mediated matrix metalloproteinase 1 participates in oral leukoplakia and carcinogenesis by inducing angiogenesis.J. Oral. Pathol. Med. 51, 638-648 (2022).
42. Hinshaw D. C.& Shevde, L. A. The tumor microenvironment innately modulates cancer progression.Cancer Res. 79, 4557-4566 (2019).
43. Mito, I.et al.Tumor-derived exosomes elicit cancer-associated fibroblasts shaping inflammatory tumor microenvironment in head and neck squamous cell carcinoma.Oral. Oncol. 136, 106270(2023).
44. Li C., Teixeira A. F., Zhu H.-J.& Ten Dijke, P. Cancer associated-fibroblast-derived exosomes in cancer progression.Mol. Cancer 20, 154(2021).
45. Sun, L.-P.et al.Cancer-associated fibroblast-derived exosomal miR-382-5p promotes the migration and invasion of oral squamous cell carcinoma.Oncol. Rep. 42, 1319-1328 (2019).
46. He, L.et al.Exosomal miR-146b-5p derived from cancer-associated fibroblasts promotes progression of oral squamous cell carcinoma by downregulating HIPK3.Cell Signal 106, 110635(2023).
47. Li, Y.-Y.et al.Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p.EBioMedicine 36, 209-220 (2018).
48. Kallinger, I.et al. Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma. Clin. Exp. Immunol. https://doi.org/10.1093/cei/uxad019 (2023).
49. Yunna C., Mengru H., Lei W.& Weidong, C. Macrophage M1/M2 polarization.Eur. J. Pharm. 877, 173090(2020).
50. Pan Y., Yu Y., Wang X.& Zhang, T. Tumor-associated macrophages in tumor immunity.Front. Immunol. 11, 583084(2020).
51. Oshi, M.et al.M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer.Sci. Rep. 10, 16554(2020).
52. Ludwig, N.et al.TGFβ+ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.J. Extracell. Vesicles 11, e12294(2022).
53. Xiao M., Zhang J., Chen W.& Chen, W. M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma.J. Exp. Clin. Cancer Res. 37, 143(2018).
54. You, Y.et al.M1-like tumor-associated macrophages cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma via the IL6/Stat3/THBS1 feedback loop.J. Exp. Clin. Cancer Res. 41, 10(2022).
55. Wu L., Ye S., Yao Y., Zhang C.& Liu, W. Oral cancer stem cell-derived small extracellular vesicles promote M2 macrophage polarization and suppress CD4+ T-cell activity by transferring UCA1 and targeting LAMC2.Stem Cells Int. 2022, 5817684(2022).
56. Manikandan, M.et al.Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism.Mol. Cancer 15, 28(2016).
57. Cai J., Qiao B., Gao N., Lin N.& He, W. Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p.Am. J. Physiol. Cell Physiol. 316, C731-C740 (2019).
58. Pang, X.et al.OSCC cell-secreted exosomal CMTM6 induced M2-like macrophages polarization via ERK1/2 signaling pathway.Cancer Immunol. Immunother. 70, 1015-1029 (2021).
59. Ono, K.et al.Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer.J. Extracell. Vesicles 9, 1769373(2020).
60. Yuan, Y.et al.Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization.Cell Commun. Signal 20, 12(2022).
61. Kumar, P., Bhattacharya, P.& Prabhakar, B. S. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.J. Autoimmun. 95, 77-99 (2018).
62. Chen, Y.et al.CircRNA has_circ_0069313 induced OSCC immunity escape by miR-325-3p-Foxp3 axes in both OSCC cells and Treg cells.Aging (Albany NY) 14, 4376-4389 (2022).
63. Johnson, D. E.et al.Head and neck squamous cell carcinoma.Nat. Rev. Dis. Prim. 6, 92(2020).
64. Ramos, A., Sadeghi, S.& Tabatabaeian, H. Battling chemoresistance in cancer: root causes and strategies to uproot them.Int. J. Mol. Sci. 22, 9451(2021).
65. Law, Z.-J.et al.Extracellular vesicle-mediated chemoresistance in oral squamous cell carcinoma.Front. Mol. Biosci. 8, 629888(2021).
66. Cheng, H.-Y.et al.Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance.J. Immunother. Cancer 10, e004832(2022).
67. Qin, X.et al.Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5.Genome Biol. 20, 12(2019).
68. Tomita R., Sasabe E., Tomomura A.& Yamamoto, T. Macrophage-derived exosomes attenuate the susceptibility of oral squamous cell carcinoma cells to chemotherapeutic drugs through the AKT/GSK-3β pathway.Oncol. Rep. 44, 1905-1916 (2020).
69. Sayyed, A. A.et al.MiR-155 inhibitor-laden exosomes reverse resistance to cisplatin in a 3D tumor spheroid and xenograft model of oral cancer.Mol. Pharm. 18, 3010-3025 (2021).
70. Kulkarni, B.et al.Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2.Oncotarget 11, 1832-1845 (2020).
71. Li, Y.et al.Irradiated cell-derived exosomes transmit essential molecules inducing radiation therapy resistance.Int. J. Radiat. Oncol. Biol. Phys. 113, 192-202 (2022).
72. Mutschelknaus, L.et al.Exosomes derived from squamous head and neck cancer promote cell survival after ionizing radiation.PLoS One 11, e0152213(2016).
73. Theodoraki, M.-N.et al.Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT.Oncoimmunology 8, 1593805(2019).
74. Theodoraki, M.-N.et al.Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.Br. J. Cancer 125, 1677-1686 (2021).
75. Vasey C.,McBride, J. & Penta, K. Circadian rhythm dysregulation and restoration: the role of melatonin.Nutrients 13, 3480(2021).
76. Wang, L., Wang, C.& Choi, W. S. Use of melatonin in cancer treatment: where are we?Int. J. Mol. Sci. 23, 3779(2022).
77. Capote-Moreno, A. et al. Potential of melatonin as adjuvant therapy of oral cancer in the era of epigenomics.Cancers (Basel) 11, 1712(2019).
78. Hunsaker, M., Barba, G., Kingsley, K. & Howard, K. M. Differential microRNA expression of miR-21 and miR-155 within oral cancer extracellular vesicles in response to melatonin. Dent. J. (Basel) 7, 48 (2019).
79. Nikanjam, M., Kato, S.& Kurzrock, R. Liquid biopsy: current technology and clinical applications.J. Hematol. Oncol. 15, 131(2022).
80. Zeng, H.et al.Current strategies for exosome cargo loading and targeting delivery.Cells 12, 1416(2023).
81. Peng, Q., Yang, J.-Y.& Zhou, G. Emerging functions and clinical applications of exosomes in human oral diseases.Cell Biosci. 10, 68(2020).
82. Slots J.Periodontitis: facts, fallacies and the future.Periodontol 2000 75, 7-23 (2017).
83. Chaparro Padilla,A. et al. Molecular signatures of extracellular vesicles in oral fluids of periodontitis patients. Oral Dis. https://doi.org/10.1111/odi.13338(2020).
84. Panni S., Lovering R. C., Porras P.& Orchard, S. Non-coding RNA regulatory networks.Biochim. Biophys. Acta Gene. Regul. Mech. 1863, 194417(2020).
85. Budakoti, M.et al.Micro-RNA: the darkhorse of cancer.Cell Signal 83, 109995(2021).
86. Nik Mohamed Kamal, N. N. S., Awang, R. A. R., Mohamad, S. & Shahidan, W. N. S. Plasma- and saliva exosome profile reveals a distinct microRNA signature in chronic periodontitis.Front. Physiol. 11, 587381(2020).
87. Kwon, E. J.et al.Profiling of plasma-derived exosomal RNA expression in patients with periodontitis: a pilot study.Oral. Dis. 29, 1726-1737 (2023).
88. Han, P.et al.TNF-α and OSX mRNA of salivary small extracellular vesicles in periodontitis: a pilot study.Tissue Eng. Part C. Methods 29, 298-306 (2023).
89. Micó-Martínez, P. et al. miR-1226 detection in GCF as potential biomarker of chronic periodontitis: a pilot study.Med. Oral. Patol. Oral. Cir. Bucal. 23, e308-e314 (2018).
90. Han P., Bartold P. M., Salomon C.& Ivanovski, S. Salivary small extracellular vesicles associated miRNAs in periodontal status—a pilot study.Int. J. Mol. Sci. 21, 2809(2020).
91. Fujimori, K.et al.Detection of salivary miRNAs reflecting chronic periodontitis: a pilot study.Molecules 24, 1034(2019).
92. Yu, J.et al.Detection of exosomal PD-L1 RNA in saliva of patients with periodontitis.Front. Genet 10, 202(2019).
93. Tobón-Arroyave, S. I., Celis-Mejía, N., Córdoba-Hidalgo, M. P. & Isaza-Guzmán, D. M. Decreased salivary concentration of CD9 and CD81 exosome-related tetraspanins may be associated with the periodontal clinical status.J. Clin. Periodontol. 46, 470-480 (2019).
94. Huang X., Hu X., Zhao M.& Zhang, Q. Analysis of salivary exosomal proteins in young adults with severe periodontitis.Oral. Dis. 26, 173-181 (2020).
95. Macey, R.et al.Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD010276.pub2 (2015).
96. Warnakulasuriya S.& Kerr, A. R. Oral cancer screening: past, present, and future.J. Dent. Res. 100, 1313-1320 (2021).
97. Zlotogorski-Hurvitz, A., Dayan, D., Chaushu, G., Salo, T. & Vered, M. Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals.J. Cancer Res. Clin. Oncol. 142, 101-110 (2016).
98. Rabinowits, G.et al.Comparative analysis of microRNA expression among benign and malignant tongue tissue and plasma of patients with tongue cancer.Front. Oncol. 7, 191(2017).
99. He, T.et al.Plasma-derived exosomal microRNA-130a serves as a noninvasive biomarker for diagnosis and prognosis of oral squamous cell carcinoma.J. Oncol. 2021, 5547911(2021).
100. Chen, C.-M.et al.Exosome-derived microRNAs in oral squamous cell carcinomas impact disease prognosis.Oral. Oncol. 120, 105402(2021).
101. Galiveti, C. R.et al.Small extravesicular microRNA in head and neck squamous cell carcinoma and its potential as a liquid biopsy for early detection.Head Neck 45, 212-224 (2023).
102. He, L.et al.Salivary exosomal miR-24-3p serves as a potential detective biomarker for oral squamous cell carcinoma screening.Biomed. Pharmacother. 121, 109553(2020).
103. Patel, A.et al.Salivary exosomal miRNA-1307-5p predicts disease aggressiveness and poor prognosis in oral squamous cell carcinoma patients.Int. J. Mol. Sci. 23, 10639(2022).
104. Farag A., Sabry D., Hassabou N.& Alaa El-din, Y. MicroRNA-134/microRNA-200a derived salivary exosomes are novel diagnostic biomarkers of oral squamous cell carcinoma.Egypt. Dent. J. 67, 367-377 (2021).
105. Faur, C. I.et al.Salivary exosomal microRNA-486-5p and microRNA-10b-5p in oral and oropharyngeal squamous cell carcinoma.Medicina (Kaunas) 58, 1478(2022).
106. Langevin, S.et al.Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers.Oncotarget 8, 82459-82474 (2017).
107. Coon, J., Kingsley, K.& Howard, K. M. miR-365 (microRNA): potential biomarker in oral squamous cell carcinoma exosomes and extracellular vesicles.Int. J. Mol. Sci. 21, 5317(2020).
108. Deng, Q.et al.Exosomal hsa_circRNA_047733 integrated with clinical features for preoperative prediction of lymph node metastasis risk in oral squamous cell carcinoma.J. Oral. Pathol. Med. 52, 37-46 (2023).
109. Xia, S.et al.Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes.Brief. Bioinform 18, 984-992 (2017).
110. Luo Y., Liu F., Guo J.& Gui, R. Upregulation of circ_0000199 in circulating exosomes is associated with survival outcome in OSCC.Sci. Rep. 10, 13739(2020).
111. Ludwig, N.et al.TGFβ carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.Br. J. Cancer 128, 1733-1741 (2023).
112. Nakamichi, E.et al.Detection of serum/salivary exosomal Alix in patients with oral squamous cell carcinoma.Oral. Dis. 27, 439-447 (2021).
113. Guo H., Jiang W., Huang S., Huang X.& Li, C. Serum exosome-derived biomarkers for the early detection of oral squamous cell carcinoma.Mol. Cell Biochem. 476, 4435-4447 (2021).
114. Li, C.et al.Potential markers from serum-purified exosomes for detecting oral squamous cell carcinoma metastasis.Cancer Epidemiol. Biomark. Prev. 28, 1668-1681 (2019).
115. Zhu, P.et al.Current status of hand-foot-and-mouth disease.J. Biomed. Sci. 30, 15(2023).
116. Jia, H.-L.et al.MicroRNA expression profile in exosome discriminates extremely severe infections from mild infections for hand, foot and mouth disease.BMC Infect. Dis. 14, 506(2014).
117. Hamour, A. F., Klieb, H.& Eskander, A. Oral lichen planus.CMAJ 192, E892(2020).
118. Peng, Q., Zhang, J.& Zhou, G. Differentially circulating exosomal microRNAs expression profiling in oral lichen planus.Am. J. Transl. Res. 10, 2848-2858 (2018).
119. Byun J.-S., Hong S.-H., Choi J.-K., Jung J.-K.& Lee, H.-J. Diagnostic profiling of salivary exosomal microRNAs in oral lichen planus patients.Oral. Dis. 21, 987-993 (2015).
120. Ding, M.et al.Distinct expression profile of HCMV encoded miRNAs in plasma from oral lichen planus patients.J. Transl. Med. 15, 133(2017).
121. Michael, A.et al.Exosomes from human saliva as a source of microRNA biomarkers.Oral. Dis. 16, 34-38 (2010).
122. Li, F.et al.Circular RNA sequencing indicates circ-IQGAP2 and circ-ZC3H6 as noninvasive biomarkers of primary Sjögren’s syndrome.Rheumatology (Oxford) 59, 2603-2615 (2020).
123. Kakan, S. S.et al.Small RNA deep sequencing identifies a unique miRNA signature released in serum exosomes in a mouse model of Sjögren’s syndrome.Front. Immunol. 11, 1475(2020).
124. Théry, C.et al.Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.J. Extracell. Vesicles 7, 1535750(2018).
125. Hiraga, C.et al.Pentapartite fractionation of particles in oral fluids by differential centrifugation.Sci. Rep. 11, 3326(2021).
126. Faur, C. I.et al.A new detection method of oral and oropharyngeal squamous cell carcinoma based on multivariate analysis of surface enhanced raman spectra of salivary exosomes.J. Pers. Med. 13, 762(2023).
127. Cheng, Y.et al.Sensitive detection of exosomes by gold nanoparticles labeling inductively coupled plasma mass spectrometry based on cholesterol recognition and rolling circle amplification.Anal. Chim. Acta 1212, 339938(2022).
128. He L., Shao M., Xu J.& Chen, H. Engineered red blood cell membrane for sensitive and precise electrochemical detection of salivary exosomes.Anal. Methods 13, 5859-5865 (2021).
129. Ruan, Z.et al.Enterovirus 71 non-structural protein 3A hijacks vacuolar protein sorting 25 to boost exosome biogenesis to facilitate viral replication.Front. Microbiol. 13, 1024899(2022).
130. Wu, J.et al.Exosomal microRNA-155 inhibits enterovirus A71 infection by targeting PICALM.Int. J. Biol. Sci. 15, 2925-2935 (2019).
131. Leiva-Sabadini, C., Alvarez, S., Barrera, N. P., Schuh, C. M. A. P. & Aguayo, S. Antibacterial effect of honey-derived exosomes containing antimicrobial peptides against oral Streptococci.Int. J. Nanomed. 16, 4891-4900 (2021).
132. Liang Y., Duan L., Lu J.& Xia, J. Engineering exosomes for targeted drug delivery.Theranostics 11, 3183-3195 (2021).
133. Ai, Y.et al.Exosomal LncRNA LBX1-AS1 derived from RBPJ overexpressed-macrophages inhibits oral squamous cell carcinoma progress via miR-182-5p/FOXO3.Front Oncol. 11, 605884(2021).
134. Wang Z., Yan J., Zou T.& Gao, H. MicroRNA-1294 inhibited oral squamous cell carcinoma growth by targeting c-Myc.Oncol. Lett. 16, 2243-2250 (2018).
135. Xie C., Du L.-Y., Guo F., Li X.& Cheng, B. Exosomes derived from microRNA-101-3p-overexpressing human bone marrow mesenchymal stem cells suppress oral cancer cell proliferation, invasion, and migration.Mol. Cell Biochem. 458, 11-26 (2019).
136. Higaki M., Shintani T., Hamada A., Rosli S. N.Z. & Okamoto, T. Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1).Vitr. Cell. Dev. Biol. Anim. 56, 222-233 (2020).
137. Deng, W.et al.In vitro experimental study on the formation of microRNA-34a loaded exosomes and their inhibitory effect in oral squamous cell carcinoma.Cell Cycle 21, 1775-1783 (2022).
138. Zhang Y., Tang K., Chen L., Du M.& Qu, Z. Exosomal CircGDI2 suppresses oral squamous cell carcinoma progression through the regulation of MiR-424-5p/SCAI Axis.Cancer Manag Res 12, 7501-7514 (2020).
139. Li K., Qiu Y., Liu X.& Huang, F. Biomimetic nanosystems for the synergistic delivery of miR-144/451a for oral squamous cell carcinoma.Balk. Med. J. 39, 178-186 (2022).
140. Rosenberger, L.et al.Stem cell exosomes inhibit angiogenesis and tumor growth of oral squamous cell carcinoma.Sci. Rep. 9, 663(2019).
141. Zhong, J.et al.High-quality milk exosomes as oral drug delivery system.Biomaterials 277, 121126(2021).
142. Zhang, Q.et al.Milk-exosome based pH/light sensitive drug system to enhance anticancer activity against oral squamous cell carcinoma.RSC Adv. 10, 28314-28323 (2020).
143. Antimisiaris, S. G., Mourtas, S.& Marazioti, A. Exosomes and exosome-inspired vesicles for targeted drug delivery.Pharmaceutics 10, 218(2018).
144. Kase, Y.et al.Engineered exosomes delivering specific tumor-suppressive RNAi attenuate oral cancer progression.Sci. Rep. 11, 5897(2021).
145. Tian, T.et al.Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy.Biomaterials 150, 137-149 (2018).
146. Tian, T.et al.Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia.Theranostics 11, 6507-6521 (2021).
147. Bai Y.-T., Zhang X.-Q., Chen X.-J.& Zhou, G. Nanomedicines in oral cancer: inspiration comes from extracellular vesicles and biomimetic nanoparticles.Nanomedicine (Lond.) 17, 1761-1778 (2022).
148. Zha, Y.et al.Exosome-mimetics as an engineered gene-activated matrix induces in-situ vascularized osteogenesis.Biomaterials 247, 119985(2020).
149. Zhai Q., Dong Z., Wang W., Li B.& Jin, Y. Dental stem cell and dental tissue regeneration.Front. Med. 13, 152-159 (2019).
150. Luo, H.et al.Advances in oral mesenchymal stem cell-derived extracellular vesicles in health and disease.Genes Dis. 11, 346-357 (2024).
151. Morsczeck C.Dental stem cells for tooth regeneration: how far have we come and where next?Expert Opin. Biol. Ther. 23, 527-537 (2023).
152. Ordinola-Zapata, R., Noblett, W. C., Perez-Ron, A., Ye, Z. & Vera, J. Present status and future directions of intracanal medicaments.Int. Endod. J. 55, 613-636 (2022).
153. Xie, Z.et al.Functional dental pulp regeneration: basic research and clinical translation.Int. J. Mol. Sci. 22, 8991(2021).
154. Huang C.-C., Narayanan R., Alapati S.& Ravindran, S. Exosomes as biomimetic tools for stem cell differentiation: applications in dental pulp tissue regeneration.Biomaterials 111, 103-115 (2016).
155. Li L.& Ge, J. Exosome-derived lncRNA-Ankrd26 promotes dental pulp restoration by regulating miR-150-TLR4 signaling.Mol. Med. Rep. 25, 152(2022).
156. Li J., Ju Y., Liu S., Fu Y.& Zhao, S. Exosomes derived from lipopolysaccharide-preconditioned human dental pulp stem cells regulate Schwann cell migration and differentiation.Connect Tissue Res. 62, 277-286 (2021).
157. Xian X., Gong Q., Li C., Guo B.& Jiang, H. Exosomes with highly angiogenic potential for possible use in pulp regeneration.J. Endod. 44, 751-758 (2018).
158. Huang, X.et al.Exosomes from LPS-stimulated hDPSCs activated the angiogenic potential of HUVECs in vitro.Stem Cells Int. 2021, 6685307(2021).
159. Chen, W.-J.et al.The role of small extracellular vesicles derived from lipopolysaccharide-preconditioned human dental pulp stem cells in dental pulp regeneration.J. Endod. 47, 961-969 (2021).
160. Li, B.et al.Hypoxia alters the proteome profile and enhances the angiogenic potential of dental pulp stem cell-derived exosomes.Biomolecules 12, 575(2022).
161. Li, B.et al.Hypoxia preconditioned DPSC-derived exosomes regulate angiogenesis via transferring LOXL2.Exp. Cell Res. 425, 113543(2023).
162. Hu, X.et al.Lineage-specific exosomes promote the odontogenic differentiation of human dental pulp stem cells (DPSCs) through TGFβ1/smads signaling pathway via transfer of microRNAs.Stem Cell Res. Ther. 10, 170(2019).
163. Brunello, G.et al.Exosomes derived from dental pulp stem cells show different angiogenic and osteogenic properties in relation to the age of the donor.Pharmaceutics 14, 908(2022).
164. Wu, M.et al.SHED aggregate exosomes shuttled miR-26a promote angiogenesis in pulp regeneration via TGF-β/SMAD2/3 signalling.Cell Prolif. 54, e13074(2021).
165. Chen, Y.et al.The application of pulp tissue derived-exosomes in pulp regeneration: a novel cell-homing approach.Int. J. Nanomed. 17, 465-476 (2022).
166. Zhuang, X.et al.Exosomes derived from stem cells from the apical papilla promote dentine-pulp complex regeneration by inducing specific dentinogenesis.Stem Cells Int. 2020, 5816723(2020).
167. Yu, S.et al.Exosomes derived from stem cells from the apical papilla alleviate inflammation in rat pulpitis by upregulating regulatory T cells.Int. Endod. J. 55, 517-530 (2022).
168. Shi, J.et al.Mesenchymal stromal cell exosomes enhance dental pulp cell functions and promote pulp-dentin regeneration.Biomater. Biosyst. 11, 100078(2023).
169. Zeng, J.et al.Exosomes from human umbilical cord mesenchymal stem cells and human dental pulp stem cells ameliorate lipopolysaccharide-induced inflammation in human dental pulp stem cells.Arch. Oral. Biol. 138, 105411(2022).
170. Bagio D. A., Julianto I., Margono A.& Suprastiwi, E. Analysis of thrombin-activated platelet-derived exosome (T-aPDE) potential for dental pulp regeneration: in-vitro study.Eur. J. Dent. 17, 173-182 (2023).
171. Kwon, T., Lamster, I. B.& Levin, L. Current concepts in the management of periodontitis.Int. Dent. J. 71, 462-476 (2021).
172. Elangovan S., Gajendrareddy P., Ravindran S.& Salem, A. K. Emerging local delivery strategies to enhance bone regeneration.Biomed. Mater. 15, 062001(2020).
173. Sun, J.et al.Exosomes derived from human gingival mesenchymal stem cells attenuate the inflammatory response in periodontal ligament stem cells.Front. Chem. 10, 863364(2022).
174. Hu, Y.et al.Human gingival mesenchymal stem cell-derived exosomes cross-regulate the Wnt/β-catenin and NF-κB signalling pathways in the periodontal inflammation microenvironment.J. Clin. Periodontol. 50, 796-806 (2023).
175. Zhang, Y.et al.Effect of gingival mesenchymal stem cell-derived exosomes on inflammatory macrophages in a high-lipid microenvironment.Int. Immunopharmacol. 94, 107455(2021).
176. Nakao, Y.et al.Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss.Acta Biomater. 122, 306-324 (2021).
177. Shen, Z.et al.Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a macrophage-dependent mechanism.Bioact. Mater. 5, 1113-1126 (2020).
178. Zhang, Y.et al.Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium.Int. J. Oral. Sci. 13, 43(2021).
179. Zheng, Y.et al.Exosomal microRNA-155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in chronic periodontitis.J. Cell. Physiol. 234, 20662-20674 (2019).
180. Kang L., Miao Y., Jin Y., Shen S.& Lin, X. Exosomal miR-205-5p derived from periodontal ligament stem cells attenuates the inflammation of chronic periodontitis via targeting XBP1.Immun. Inflamm. Dis. 11, e743(2023).
181. Tomokiyo, A., Wada, N.& Maeda, H. Periodontal ligament stem cells: regenerative potency i