Organoid-tissue extracellular vesicles

Abstract

Extracellular vesicles (EVs) are lipid bilayer structures secreted by cells that act as intercellular messengers. Tissue-derived EVs (TEVs), harvested from the tissue interstitium, directly reflect the actual physiological or pathological state of the tissue microenvironment. However, the difficulty in tissue acquisition severely limits the development of TEVs. In contrast, organoids are 3D cell clusters cultured from stem cells, which have spatial structures and physiological functions that are highly similar to the source tissues. Although organoid-derived EVs (OEVs), isolated from culture supernatants, can reflect complex cellular interactions, they cannot directly reflect the state of the tissue microenvironment like TEVs. Building on the foundation of TEVs and OEVs, we introduce the innovative concept of organoid-tissue EVs (OTEVs), where residing in the organoid interstitium. Acting as a communication bridge between OEVs and TEVs, OTEVs can accurately represent the true microenvironment. They overcome the challenges associated with the limited availability of TEVs and the inability of OEVs to directly reflect the microenvironment. We believe that OTEVs will synergize with TEVs and OEVs to enhance the understanding of the pathogenesis of complex diseases, as well as to improve their diagnosis and treatment.

Keywords

diseases diagnosis and treatment / extracellular vesicles / organoid extracellular vesicles / tissue extracellular vesicles

References

[1] X. Liu, Q. Wei, Z. Sun, S. Cui, X. Wan, Z. Chu, Y. Zhang, W. Zhong, L. Lu, L. Shi, X. Fu, C. Zhang, S. Wang, Interdiscip. Med. 2023, 1, e20230019.

[2] H. Liu, Q. Zhang, S. Wang, W. Weng, Y. Jing, J. Su, Bioact. Mater. 2022, 14, 169.

[3] H. Liu, Z. Geng, J. Su, Extracell Vesicles Circ. Nucl. Acids 2022, 3, 63.

[4] H. Liu, M. Li, T. Zhang, X. Liu, H. Zhang, Z. Geng, J. Su, Chem. Eng. J 2022, 450, 138309.

[5] X. Liu, Q. Wei, L. Lu, S. Cui, K. Ma, W. Zhang, F. Ma, H. Li, X. Fu, C. Zhang, Front. Immunol. 2023, 14, 1094685.

[6] Q. Wei, X. Liu, J. L. Su, Y. X. Wang, Z. Q. Chu, K. Ma, Q. L. Huang, H. H. Li, X. B. Fu, C. P. Zhang, Front. Bioeng. Biotechnol. 2022, 10, 1083459.

[7] H. Liu, H. Zhang, Y. Han, Y. Hu, Z. Geng, J. Su, Theranostics 2022, 12, 6576.

[8] H. Liu, H. Zhang, S. Wang, J. Cui, W. Weng, X. Liu, H. Tang, Y. Hu, X. Li, K. Zhang, F. Zhou, Y. Jing, J. Su, Compos. Part B Eng. 2023, 255, 110610.

[9] Q. Wei, J. Su, S. Meng, Y. Wang, K. Ma, B. Li, Z. Chu, Q. Huang, W. Hu, Z. Wang, L. Tian, X. Liu, T. Li, X. Fu, C. Zhang, Adv. Sci. 2024, 11, 2307761.

[10] H. Liu, J. Sun, M. Wang, S. Wang, J. Su, C. Xu, Chem. Eng. J 2023, 465, 142842.

[11] H. Liu, J. Su, Interdiscip. Med. 2023, 1, e20230011.

[12] L. S. Holliday, J. K. Neubert, X. Yang, Extracell Vesicles Circ. Nucl. Acids 2025, 6, 158.

[13] J. C. Lee, R. M. Ray, T. A. Scott, Mol. Ther. 2024, 32, 2950.

[14] S. R. Li, Q. W. Man, X. Gao, H. Lin, J. Wang, F. C. Su, H. Q. Wang, L. L. Bu, B. Liu, G. Chen, J. Extracell. Vesicles 2021, 10, e12175.

[15] K. S. Lee, J. Lee, H. K. Kim, S. H. Yeom, C. H. Woo, Y. J. Jung, Y. E. Yun, S. Y. Park, J. Han, E. Kim, J. H. Sul, J. M. Jung, J. H. Park, J. S. Choi, Y. W. Cho, D. G. Jo, J. Extracell. Vesicles 2021, 10, e12152.

[16] B. Yin, J. Ni, C. E. Witherel, M. Yang, J. A. Burdick, C. Wen, S. H. D. Wong, Theranostics 2022, 12, 207.

[17] P. Lou, S. Liu, Y. Wang, K. Lv, X. Zhou, L. Li, Y. Zhang, Y. Chen, J. Cheng, Y. Lu, J. Liu, Adv. Mater. 2023, 35, 2300602.

[18] B. Li, Y. Jin, B. Zhang, T. Lu, J. Li, J. Zhang, Y. Zhou, Y. Wang, C. Zhang, Y. Zhao, H. Li, Clin. Transl. Med. 2024, 14, e70029.

[19] Z. Ye, W. Chen, G. Li, J. Huang, J. Lei, Cancer Metastasis Rev. 2024, 43, 575.

[20] R. Polak, E. T. Zhang, C. J. Kuo, Nat. Rev. Cancer 2024, 24, 523.

[21] Z. Zhao, X. Chen, A. M. Dowbaj, A. Sljukic, K. Bratlie, L. Lin, E. L. S. Fong, G. M. Balachander, Z. Chen, A. Soragni, M. Huch, Y. A. Zeng, Q. Wang, H. Yu, Nat. Rev. Methods Primers 2022, 2, 94.

[22] C. Corrò, L. Novellasdemunt, V. S. W. Li, Am. J. Physiol. Cell Physiol 2020, 319, C151.

[23] H. Liu, J. Su, Biomater. Transl 2023, 4, 199.

[24] G. Zhou, R. Li, S. Sheng, J. Huang, F. Zhou, Y. Wei, H. Liu, J. Su, J. Nanobiotechnol. 2024, 22, 679.

[25] H. Liu, J. T. Triffitt, Z. Xia, J. Su, Biomater. Transl 2024, 5, 93.

[26] N. Ji, F. Wang, M. Wang, W. Zhang, H. Liu, J. Su, J. Control. Release 2023, 364, 46.

[27] H. Liu, P. Song, H. Zhang, F. Zhou, N. Ji, M. Wang, G. Zhou, R. Han, X. Liu, W. Weng, H. Tan, S. Wang, L. Zheng, Y. Jing, J. Su, J. Extracell. Vesicles 2024, 13, e12429.

[28] H. Liu, Y. Wu, F. Wang, S. Wang, N. Ji, M. Wang, G. Zhou, R. Han, X. Liu, W. Weng, H. Tan, Y. Jing, W. Zhang, H. Zhang, Z. Shi, J. Su, Compos. Part B Eng. 2023, 267, 111047.

[29] H. Liu, R. Li, H. Yang, B. Situ, G. Wang, K. Xu, J. Su, Small Sci. 2025, 5, 2400474.

[30] M. Ravi, V. Paramesh, S. R. Kaviya, E. Anuradha, F. D. Solomon, J. Cell. Physiol. 2015, 230, 16.

[31] R. Crescitelli, C. Lässer, J. Lötvall, Nat. Protoc. 2021, 16, 1548.

[32] M. A. Kumar, S. K. Baba, H. Q. Sadida, S. A. Marzooqi, J. Jerobin, F. H. Altemani, N. Algehainy, M. A. Alanazi, A. B. Abou-Samra, R. Kumar, A. S. Al-Shabeeb Akil, M. A. Macha, R. Mir, A. A. Bhat, Signal Transduct Target Ther. 2024, 9, 27.

[33] W. Li, J. Zhu, J. Li, Y. Jiang, J. Sun, Y. Xu, H. Pan, Y. Zhou, J. Zhu, J. Cancer Res. Clin. Oncol. 2024, 150, 184.

[34] L. Jank, A. Kesharwani, T. Ryu, D. Joshi, D. C. Ladakis, M. D. Smith, S. Singh, T. Arab, K. W. Witwer, P. A. Calabresi, C. H. Na, P. Bhargava, J. Neuroinflammation 2024, 21, 154.

[35] L. Debbi, S. Guo, D. Safina, S. Levenberg, Biotechnol. Adv. 2022, 59, 107983.

[36] Y. Xia, J. Zhang, G. Liu, J. Wolfram, Adv. Mater. 2024, 36, 2403199.

[37] Y. Li, H. Zhang, Y. Jiang, J. Yang, D. Cai, X. Bai, Interdiscip. Med. 2024, 2, e20230055.

[38] J. Han, S. Kim, Y. H. Hwang, S. A. Kim, Y. Lee, J. Kim, S. Cho, J. Woo, C. Jeong, M. Kwon, G. H. Nam, I. S. Kim, Adv. Sci. 2024, 11, 2308662.

[39] J. Dong, B. Wu, W. Tian, Stem Cell Res. Ther. 2023, 14, 67.

[40] L. Dong, M. Feng, M. D. Kuczler, K. Horie, C. J. Kim, Z. Ma, K. Lombardo, H. Lyons, S. R. Amend, M. Kates, T. J. Bivalacqua, D. McConkey, W. Xue, W. Choi, K. J. Pienta, J. Extracell. Vesicles 2024, 13, e12402.

[41] A. S. Rizzuto, G. Gelpi, A. Mangini, S. Carugo, M. Ruscica, C. Macchi, iScience 2024, 27, 109359.

[42] V. Bodart-Santos, L. S. Pinheiro, A. J. da Silva-Junior, R. L. Froza, R. Ahrens, R. A. Gonçalves, M. M. Andrade, Y. Chen, C. L. Alcantara, L. T. Grinberg, R. E. P. Leite, S. T. Ferreira, P. E. Fraser, F. G. De Felice, Alzheimers Dement 2023, 19, 5418.

[43] S. Muraoka, A. M. DeLeo, M. K. Sethi, K. Yukawa-Takamatsu, Z. Yang, J. Ko, J. D. Hogan, Z. Ruan, Y. You, Y. Wang, M. Medalla, S. Ikezu, M. Chen, W. Xia, S. Gorantla, H. E. Gendelman, D. Issadore, J. Zaia, T. Ikezu, Alzheimers Dement 2020, 16, 896.

[44] I. Jeong, S. Park, J. Park, O. K. Kim, Food Nutr. Res. 2024, 68, 10545.

[45] S. Q. Ying, Y. Cao, Z. K. Zhou, X. Y. Luo, X. H. Zhang, K. Shi, J. Y. Qiu, S. J. Xing, Y. Y. Li, K. Zhang, F. Jin, C. X. Zheng, Y. Jin, B. D. Sui, J. Nanobiotechnol. 2024, 22, 521.

[46] S. Ma, X. Xing, H. Huang, X. Gao, X. Xu, J. Yang, C. Liao, X. Zhang, J. Liu, W. Tian, L. Liao, Cell Metab. 2023, 35, 2028.

[47] A. F. Deng, F. X. Wang, S. C. Wang, Y. Z. Zhang, L. Bai, J. C. Su, Mil. Med. Res. 2024, 11, 37.

[48] V. V. T. Nguyen, S. Ye, V. Gkouzioti, M. E. van Wolferen, F. Y. Yengej, D. Melkert, S. Siti, B. de Jong, P. J. Besseling, B. Spee, L. J. W. van der Laan, R. Horland, M. C. Verhaar, B. W. M. van Balkom, J. Extracell. Vesicles 2022, 11, e12280.

[49] S. Abdollahi, Biotechnol. Bioeng. 2021, 118, 1029.

[50] P. Arthur, S. Kandoi, L. Sun, A. Kalvala, S. Kutlehria, S. Bhattacharya, T. Kulkarni, R. Nimma, Y. Li, D. A. Lamba, M. Singh, Pharm. Res. 2023, 40, 801.

[51] S. Huang, Y. Zeng, Q. Guo, T. Zou, Z. Q. Yin, J. Control. Release 2024, 370, 405.

[52] L. Ye, Y. Wang, F. Xiao, X. Wang, X. Li, R. Cao, J. Zhang, T. Zhang, Microb. Cell Fact. 2023, 22, 235.

[53] Y. Zhang, Y. Yan, J. Meng, M. Girotra, S. Ramakrishnan, S. Roy, Mucosal Immunol. 2021, 14, 887.

[54] A. Chansaenroj, C. Adine, S. Charoenlappanit, S. Roytrakul, L. Sariya, T. Osathanon, S. Rungarunlert, G. Urkasemsin, R. Chaisuparat, S. Yodmuang, G. R. Souza, J. N. Ferreira, Bioact. Mater. 2022, 18, 151.

[55] S. Kwak, C. L. Song, J. Lee, S. Kim, S. Nam, Y. J. Park, J. Lee, Biomaterials 2024, 307, 122522.

[56] H. Gao, Y. Zeng, X. Huang, L. A, Q. Liang, J. Xie, X. Lin, J. Gong, X. Fan, T. Zou, H. Xu, J. Extracell. Vesicles 2024, 13, e12401.

[57] B. S. Beydag-Tasöz, S. Yennek, A. Grapin-Botton, Nat. Rev. Endocrinol. 2023, 19, 232.

[58] J. Wang, Y. Wu, G. Li, F. Zhou, X. Wu, M. Wang, X. Liu, H. Tang, L. Bai, Z. Geng, P. Song, Z. Shi, X. Ren, J. Su, Adv. Mater. 2024, 36, 2309875.

[59] Y. Hu, H. Zhang, S. Wang, L. Cao, F. Zhou, Y. Jing, J. Su, Bioact. Mater. 2023, 25, 29.

[60] L. Bai, Y. Wu, G. Li, W. Zhang, H. Zhang, J. Su, Bioact. Mater. 2024, 31, 525.

[61] Y. Li, C. Zhou, H. Liu, T. Cai, H. Fan, Biomolecules 2024, 14, 312.

[62] R. Han, Y. Wu, Y. Han, X. Liu, H. Liu, J. Su, Nano Res. 2024, 17, 2857.

[63] R. Huang, B. Jia, D. Su, M. Li, Z. Xu, C. He, Y. Huang, H. Fan, H. Chen, F. Cheng, J. Extracell. Vesicles 2023, 12, e12361.

[64] R. Han, D. Zhou, N. Ji, Z. Yin, J. Wang, Q. Zhang, H. Zhang, J. Liu, X. Liu, H. Liu, Q. Han, J. Su, J. Nanobiotechnol. 2025, 23, 41.

[65] J. Feng, Q. Xiu, Y. Huang, Z. Troyer, B. Li, L. Zheng, Adv. Mater. 2023, 35, 2207826.

[66] Y. Cao, Z. Wu, H. Li, J. Shen, D. Li, T. Qiu, Z. Chen, Q. Zhao, K. Zhao, Extracell Vesicles Circ. Nucl. Acids 2025, 6, 21.

[67] Y. Chen, Z. Ou, M. Pang, Z. Tao, X. Zheng, Z. Huang, D. Wen, Q. Li, R. Zhou, P. Chen, B. Situ, C. Sheng, Y. Huang, X. Yue, L. Zheng, L. Huang, J. Extracell. Vesicles 2023, 12, e12328.

[68] Z. Ou, B. Situ, X. Huang, Y. Xue, X. He, Q. Li, D. Ou, B. He, J. Chen, Y. Huang, L. Deng, M. Zhang, Q. Wang, L. Zheng, J. Extracell. Vesicles 2023, 12, e12395.

[69] Y. Lin, J. Wang, F. Bu, R. Zhang, J. Wang, Y. Wang, M. Huang, Y. Huang, L. Zheng, Q. Wang, X. Hu, Gut Microbes 2025, 17, 2452229.

[70] S. Wang, Y. Hu, P. Song, Q. Lin, X. Tang, Q. Gao, J. Wang, D. Zhou, J. Li, D. Huang, L. Bai, X. Chen, J. Gao, H. Liu, Z. Shi, J. Su, Compos. Part B Eng. 2025, 297, 112255.

[71] M. Wen, J. Wang, Z. Ou, G. Nie, Y. Chen, M. Li, Z. Wu, S. Xiong, H. Zhou, Z. Yang, G. Long, J. Su, H. Liu, Y. Jing, Z. Wen, Y. Fu, T. Zhou, H. Xie, W. Guan, X. Sun, Z. Wang, J. Wang, X. Chen, L. Jiang, X. Qin, Y. Xue, M. Huang, X. Huang, R. Pan, H. Zhen, Y. Du, Q. Li, X. Huang, Y. Wu, P. Wang, K. Zhao, B. Situ, X. Hu, L. Zheng, Interdiscip. Med. 2023, 1, e20230017.

[72] Y. Ma, S. Dong, A. J. Grippin, L. Teng, A. S. Lee, B. Y. S. Kim, W. Jiang, Trends Biotechnol. 2025, 43, 61.

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2025 The Author(s). Interdisciplinary Medicine published by Wiley-VCH GmbH on behalf of Nanfang Hospital, Southern Medical University.