Holistic bone developing microenvironment engineered apoptotic extracellular vesicles recapitulate multidimensional developmental signatures in adult and senile bone repair

Xiaoran Yu; Jieyun Xu; Yuan Zhao; Xinyu Guo; Hongcheng Chen; Junlong Xue; Yong Ao; Linjun Zhang; Xiaomeng Gao; Xueli Mao; Songtao Shi; Zetao Chen

doi:10.1002/inmd.70109

Interdisciplinary Medicine ›› 2026, Vol. 4 ›› Issue (4) :e70109 DOI: 10.1002/inmd.70109

RESEARCH ARTICLE

Holistic bone developing microenvironment engineered apoptotic extracellular vesicles recapitulate multidimensional developmental signatures in adult and senile bone repair

Author information +

History +

PDF (7606KB)

Abstract

Owing to the rich repertoire of bioactive cargos inherited from parent cells, apoptotic extracellular vesicles (ApoEVs) have emerged as powerful biological agents in regenerative medicine. To augment ApoEVs regenerative potency, microenvironment-engineered ApoEVs (ME-ApoEVs) have been proposed, which mainly focused on embedding a single microenvironment factor within the vesicle cargo. Since the microenvironment operates as a system composed of multiple factors that collectively govern regeneration, we introduce a novel holistic microenvironment-engineered ApoEVs (hME-ApoEVs) for superior ME-ApoEVs. To validate the hME-ApoEV concept, we endowed ApoEV with a bone developing microenvironment, aiming to recapitulate developing features in adult bone repair. In the study, the developing bone microenvironment was first identified as an M2a-like macrophage driven immune microenvironment accounting for multidimensional developmental signatures. Based on these findings, we successfully fabricated hME-ApoEVs via stimulating the M2a-like developing microenvironment in vitro and confirmed its recapitulation of developmental signatures. Thirdly, we found that hME-ApoEVs recapitulated multidimensional developmental signatures in bone marrow-derived mesenchymal stem cell (BMSC) likely through activating Wnt/β-catenin signaling pathway. Finally, hME-ApoEVs were verified to retain development signatures in adult and senile cranial bone repair, improving bone regeneration. Instead of engineering a single microenvironment factor, the hME-ApoEV strategy effectively recapitulated the key features of the desired microenvironment in themselves, target cells and animal models via imprinting key features onto a simulated microenvironment generated by key cells in vitro. This strategy equips ApoEVs with complex microenvironment cues, amplifying their potency in regeneration medicine and providing a promising foundation for future microenvironment-inspired ApoEV engineering strategies.

Keywords

apoptotic extracellular vesicles / holistic microenvironment engineering strategy / multidimensional developmental signatures / senile bone repairing / Wnt/β-catenin signaling pathway

Cite this article

Download citation ▾

Xiaoran Yu, Jieyun Xu, Yuan Zhao, Xinyu Guo, Hongcheng Chen, Junlong Xue, Yong Ao, Linjun Zhang, Xiaomeng Gao, Xueli Mao, Songtao Shi, Zetao Chen. Holistic bone developing microenvironment engineered apoptotic extracellular vesicles recapitulate multidimensional developmental signatures in adult and senile bone repair. Interdisciplinary Medicine, 2026, 4 (4) : e70109 DOI:10.1002/inmd.70109

登录浏览全文

4963

注册一个新账户忘记密码

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	A. Kawasumi-Kita, S. W. Lee, D. Ohtsuka, K. Niimi, Y. Asakura, K. Kitajima, Y. Sakane, K. Tamura, H. Ochi, K. T. Suzuki, Y. Morishita, Nat. Commun. 2024, 15, 3340.

[2]	H. K. C. Co, C. C. Wu, Y. C. Lee, S. H. Chen, Nature 2024, 631, 654.

[3]	M. Yusupova, R. Ankawa, Y. Yosefzon, D. Meiri, I. Bachelet, Y. Fuchs, Nat. Commun. 2023, 14, 7547.

[4]	A. Amiri, R. Bagherifar, E. A. Dezfouli, S. H. Kiaie, R. Jafari, R. Ramezani, J. Transl. Med. 2022, 20, 25.

[5]	Q. Ye, X. Qiu, J. Wang, B. Xu, Y. Su, C. Zheng, L. Gui, L. Yu, H. Kuang, H. Liu, X. He, Z. Ma, Q. Wang, Y. Jin, Int. J. Oral Sci. 2023, 15, 7.

[6]	Y. Zhu, X. Chen, Y. Liao, Stem Cell. 2023, 41, 837.

[7]	D. M. Vu, V. T. Nguyen, T. H. Nguyen, P. T. X. Do, H. H. Dao, D. X. Hai, N. T. Le, X. H. Nguyen, U. T. T. Than, Biomedicines 2022, 10, 1810.

[8]	Z. Ding, Z. Yan, X. Yuan, G. Tian, J. Wu, L. Fu, H. Yin, S. He, C. Ning, Y. Zheng, Z. Zhang, X. Sui, L. Hao, Y. Niu, S. Liu, W. Guo, Q. Guo, J. Nanobiotechnol. 2024, 22, 74.

[9]	S. Qian, J. Mao, Q. Zhao, B. Zhao, Z. Liu, B. Lu, L. Zhang, X. Mao, Y. Zhang, D. Wang, X. Sun, W. Cui, Sci. Bull. 2023, 68, 826.

[10]	X. Zhou, J. Xue, Y. Zhang, R. Xia, Z. Shan, L. Zhang, M. Gui, G. Liu, Z. Chen, Biomater. Res. 2025, 29, 0131.

[11]	Z. Han, Y. Lin, X. Guo, J. Xu, X. Gao, R. Yang, Y. Zhao, M. Gui, L. Zhang, Y. Guo, Z. Chen, Adv. Healthcare Mater. 2024, 13, 2403122.

[12]	M. Desgres, P. Menasché, Cell Stem Cell 2019, 25, 594.

[13]	H. Zhang, J. Hao, H. Hong, W. Gu, Z. Li, J. Sun, H. Zhan, X. Wei, L. Zhou, Biotechnol. Genet. Eng. Rev. 2024, 40, 2308.

[14]	P. Smeriglio, A. Zalc, Curr. Osteoporos. Rep. 2023, 21, 624.

[15]	N. Su, C. Villicana, F. Yang, Biomaterials 2022, 286, 121604.

[16]	G. Gula, A. Ratajska, Dev. Biol. 2022, 488, 1.

[17]	G. Liu, L. Zhang, X. Zhou, J. Xue, R. Xia, X. Gan, C. Lv, Y. Zhang, X. Mao, X. Kou, S. Shi, Z. Chen, J. Adv. Res. 2024, 60, 233.

[18]	C. Vicidomini, N. Guo, A. Sahay, Neuron 2020, 105, 220.

[19]	B.-D. Sui, C.-X. Zheng, W.-M. Zhao, K. Xuan, B. Li, Y. Jin, Physiol. Rev. 2023, 103, 1899.

[20]	S. Fujimori, H. Novak, M. Weissenböck, M. Jussila, A. Gonçalves, R. Zeller, J. Galloway, I. Thesleff, C. Hartmann, Dev. Biol. 2010, 348, 97.

[21]	S. Oka, K. Oka, X. Xu, T. Sasaki, P. Bringas, Y. Chai, Mech. Dev. 2007, 124, 409.

[22]	T. Lawrence, G. Natoli, Nat. Rev. Immunol. 2011, 11, 750.

[23]	L. Batoon, A. J. Koh, S. M. Millard, J. Grewal, F. M. Choo, R. Kannan, A. Kinnaird, M. Avey, T. Teslya, A. R. Pettit, L. K. McCauley, H. Roca, Bone Res. 2024, 12, 43.

[24]	D. Liu, X. Kou, C. Chen, S. Liu, Y. Liu, W. Yu, T. Yu, R. Yang, R. Wang, Y. Zhou, S. Shi, Cell Res. 2018, 28, 918.

[25]	Q. Ou, X. Qiao, Z. Li, L. Niu, F. Lei, R. Cheng, T. Xie, N. Yang, Y. Liu, L. Fu, J. Yang, X. Mao, X. Kou, C. Chen, S. Shi, Cell Metab. 2024, 36, 78.

[26]	Z. Huang, Y. Zhuang, W. Li, M. Ma, F. Lei, Y. Qu, J. Li, H. Luo, C. Li, L. Lu, L. Ma, X. Zhang, X. Kou, L. Jiang, X. Mao, S. Shi, J. Extracell. Vesicles 2024, 13, e12428.

[27]	Y. Qu, Y. He, B. Meng, X. Zhang, J. Ding, X. Kou, W. Teng, S. Shi, Acta Biomater. 2022, 149, 258.

[28]	R. Nusse, H. Clevers, Cell 2017, 169, 985.

[29]	R. S. Lach, C. Qiu, E. Z. Kajbaf, N. Baxter, D. Han, A. Wang, H. Lock, O. Chirikian, B. Pruitt, M. Z. Wilson, Proc. Natl. Acad. Sci. USA 2022, 119, e2204688119.

[30]	H. Clevers, Cell 2006, 127, 469.

[31]	R. Baron, M. Kneissel, Nat. Med. 2013, 19, 179.

[32]	B. Chen, M. E. Dodge, W. Tang, J. Lu, Z. Ma, C. W. Fan, S. Wei, W. Hao, J. Kilgore, N. S. Williams, M. G. Roth, J. F. Amatruda, C. Chen, L. Lum, Nat. Chem. Biol. 2009, 5, 100.

[33]	S. Jiang, L. Zhu, H. Tang, M. Zhang, Z. Chen, J. Fei, B. Han, G. M. Zou, Int. J. Oncol. 2015, 47, 610.

[34]	G. Zhu, Y. Wang, B. Huang, J. Liang, Y. Ding, A. Xu, W. Wu, Oncogene 2012, 31, 1001.

[35]	Q. Wu, Y. Wang, M. Qian, Y. Qiao, S. Zou, C. Chen, X. Zhang, Y. Chen, Y. Zhao, G. Zhu, Y. Chen, F. Sun, J. Wang, Q. Pan, Cell. Signal. 2017, 37, 62.

[36]	T. Goretsky, E. M. Bradford, H. Ryu, M. Tahir, M. P. Moyer, T. Gao, L. Li, T. A. Barrett, J. Biol. Chem. 2016, 291, 4166.

[37]	J. Xu, X. Yu, H. Chen, J. Xue, Z. Gong, Z. Shan, S. Chen, Y. Guo, X. Gao, L. Zhang, Y. Xiao, F. Deng, Z. Chen, Small Structures 2025, 6, 2400499.

[38]	Y. Jiang, X. Li, R. Huang, F. Lei, L. Li, B. Yang, W. Zen, H. Tan, Y. Huang, J. Hu, Y. Xiong, Z. Wang, Z. Chen, L. Chen, S. Shi, X. Mao, Mol. Ther. 2025, 33, 2931.