2. Academic Validation
  3. 3D Nanofibrillar Matrix Stiffness Modulates Extracellular Vesicle Cargo and Pro-Tumour Functions

3D Nanofibrillar Matrix Stiffness Modulates Extracellular Vesicle Cargo and Pro-Tumour Functions

  • J Extracell Vesicles. 2025 Oct;14(10):e70165. doi: 10.1002/jev2.70165.
Zesheng Wang 1 2 3,  Xulin Xie 1,  Yicen Zhou 1,  Huimin He 4,  Zhenjun Guo 5,  Zhengdong Zhou 1,  Beilei Liu 1,  Jiayu Sun 6 7,  Wenxiu Li 1,  Qichang Nie 1,  Jun Dai 1,  Wenkai Yi 1,  Xiaoyu Zhou 1 2 3,  Jian Yan 1,  Mengsu Yang 1 2 3
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
  • 2 Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, China.
  • 3 Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Matter Science Research Institute (Futian), Shenzhen, China.
  • 4 Institute for Frontier Science, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
  • 5 Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6 State Key Laboratory of Precision and Intelligent Chemistry, Hefei, Anhui, China.
  • 7 Department of Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, China.
PMID: 41063444 DOI: 10.1002/jev2.70165
Abstract

Extracellular matrix (ECM) stiffness and extracellular vesicles (EVs) are critical regulators of tumour progression, yet their interaction in three-dimensional (3D) microenvironments remains poorly understood. Most studies on ECM stiffness and EV biology rely on 2D cultures, which do not capture the complexity of the tumour microenvironment. Here, a biomimetic 3D nanofibrillar ECM model based on a cellulose nanofibril hydrogel was established to assess stiffness-dependent changes in EV properties and functions. EVs derived from stiff matrices (StEVs) exhibited distinct physicochemical characteristics and carried unique protein and MicroRNA cargo compared with those from soft matrices (SoEVs). Functionally, StEVs more potently promoted tumour cell proliferation and migration, while in vivo mouse models further demonstrated that StEVs enhanced tumour growth. Multi-omics analyses and pharmacological inhibition studies revealed that StEVs activate the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) signalling pathway in recipient cells. These findings highlight the mechanobiological regulation of EV-mediated intercellular communication within 3D ECM environments and demonstrate how matrix stiffness shapes EV cargo and pro-tumour activity.

Keywords

cellulose nanofibril; extracellular vesicles; stiffness; three‐dimensional (3D); tumour microenvironment.

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