Harnessing the mechanical microenvironment to optimize mesenchymal stem/stromal cells (MSCs) extracellular vesicle therapeutics

Sep 29, 2026

Cell-free therapies are reshaping regenerative medicine, with extracellular vesicles (EVs) emerging as promising alternatives to direct stem cell transplantation. Mesenchymal stem/stromal cells (MSCs) are a leading EV source, yet the therapeutic performance of MSC-derived EVs depends on optimizing the culture microenvironment. Mechanical cues in three-dimensional systems govern MSC behavior and the quality, cargo, and bioactivity of secreted EVs. Kang et al. demonstrates that tuned hydrogel mechanics can shift EV angiogenic and immunomodulatory functions, guiding future EV-based therapeutic design.

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Editorial Commentary | Emerging Medical Technology Innovation and Translation

Harnessing the mechanical microenvironment to optimize MSC extracellular vesicle therapeutics

Key findings and mechanistic implications

Editorial Commentary | Emerging Medical Technology Innovation and Translation Harnessing the mechanical microenvironment to optimize mesenchymal stem/stromal cells (MSCs) extracellular vesicle therapeutics Enrico Ragni1, Laura de Girolamo1, Dimitrios Kouroupis2,3^ 1Laboratorio di Biotecnologie Applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 2Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, USA; 3Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, Miami, FL, USA Correspondence to: Dimitrios Kouroupis, MSc, PhD. Department of Orthopaedics, UHealth Sports Medicine Institute, University of Miami, Miller School of Medicine, Miami, FL, USA; Diabetes Research Institute and Cell Transplantation Center, University of Miami, Miller School of Medicine, 1450NW 10th Ave, Room 3014, Miami, FL 33136, USA. Email: [dxk504@med.miami.edu](dxk504@med.miami.edu). Comment on: Kang WY, Jung S, Jeong H, et al. Effect of Mechanical Environment Alterations in 3D Stem Cell Culture on the Therapeutic Potential of Extracellular Vesicles. Biomater Res 2025;29:0189 . Keywords: Stem cells; regenerative medicine; extracellular vesicles (EVs) Submitted Sep 29, 2025. Accepted for publication Nov 12, 2025. Published online Dec 23, 2025. doi: 10.21037/atm-25-145 View this article at: [https://dx.doi.org/10.21037/atm-25-145](https://dx.doi.org/10.21037/atm-25-145) The advent of cell-free therapies has revolutionized regenerative medicine, positioning extracellular vesicles (EVs) as promising alternatives to direct stem cell transplantation. Among the diverse stem cell sources, mesenchymal stem/stromal cells (MSCs) have emerged as a leading candidate for EV production, owing to their relative ease of isolation, robust immunomodulatory capabilities, and broad tissue repair potential (1-7) . Despite these advantages, the full therapeutic utility of MSC-derived EVs (MSC-EVs) remains contingent on optimizing the cellular microenvironment during culture. In particular, the mechanical cues within three-dimensional (3D) culture systems critically influence MSC behavior and the quality and function of their secreted EVs. In recent years, this concept has gained growing attention, as demonstrated by an increasing number of studies and clinical trials exploring mechanically conditioned MSC-EVs for applications ranging from musculoskeletal repair to cardiovascular and neurological regeneration. In this context, the study by Kang et al. (8) offers timely and compelling insight into the critical role of mechanical cues in shaping the therapeutic potential of EVs derived from stem cells cultured in 3D environments. The authors engineer a series of tunable 3D hydrogel systems with varying mechanical properties to culture stem cells and assess the resultant EVs in terms of molecular cargo and functional activity. Their findings showed that subtle differences in matrix mechanical stiffness and viscoelasticity lead to significant alterations in the angiogenic and immunomodulatory functions of the released EVs. These results reinforce a key concept increasingly recognized in the field of regenerative medicine—that mechanotransduction, the cellular process of converting mechanical signals into biochemical activity, is not only a determinant of stem cell fate (9-11), but also a modulator of the paracrine factors they secrete, including EVs. By adopting a rigorous experimental design and a multidimensional analytical approach, Kang et al. also provide a valuable framework for future investigations aiming to dissect the link between mechanical conditioning and EV functionality, a critical step toward the rational design of EV-based therapeutics. MSCs are inherently mechanosensitive cells that ^ ORCID: 0000-0002-3892-9013. © AME Publishing Company. Ann Transl Med 2025;13(6):67 | [https://dx.doi.org/10.2103

FAQs

Why are extracellular vesicles (EVs) considered promising for regenerative medicine?

EVs provide a cell-free approach to regenerative therapy, positioned as alternatives to direct stem cell transplantation. The article highlights MSC-derived EVs as especially compelling due to isolation feasibility and immunomodulatory and repair potential.

How does the mechanical microenvironment influence MSC-derived EVs?

Within 3D culture systems, mechanical cues shape MSC behavior and change the quality and function of EVs they release. The commentary emphasizes that matrix stiffness and viscoelasticity can significantly alter EV angiogenic and immunomodulatory activity.

What future questions does the editorial raise about mechanically conditioned MSC-EVs?

The commentary asks about durability of functional enhancements in vivo, how additional mechanical stimuli (beyond stiffness) affect EV cargo and release, and whether preconditioning introduces tradeoffs in EV functionality or safety.

Sep 29, 2026

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