Abstract
Low retention of transplanted stem cells at target sites remains a major barrier to the clinical translation of cell-based therapies. Conventional strategies, including genetic modification, chemical functionalization, and biomaterial encapsulation, often face limitations in translational feasibility, safety, or procedural complexity. Here, we present a nanoparticle-enabled biophysical approach to enhance cell retention. We incorporate cell-settling nanoparticles composed of clinically approved materials into mesenchymal stem cells, increasing cellular density to accelerate gravitational settling and improve adhesion and survival. Building on this, we develop copper-chaperone-activatable nanoparticles, which enhance tissue regeneration and anti-fibrotic signaling through activation of fibroblast growth factor 2 and a positive feedback loop. In a mouse skin wound model, we show that copper-chaperone-activatable nanoparticle-treated mesenchymal stem cells exhibit enhanced vascularization and reduced fibrosis. These findings demonstrate that modulation of cellular density and physical forces can improve stem cell engraftment, establishing a biophysical framework for safe and translationally relevant cell-based therapies.
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Acknowledgements
S.H.B discloses support for the research of this work from the Korean Fund for Regenerative Medicine (KFRM) grant (KFRM 21A0102L1-22), funded by the Ministry of Science and ICT, Republic of Korea. This work is also supported by the Alchemist Project of the Korea Evaluation Institute of Industrial Technology (KEIT 20018560, NTIS 2410005252), the Ministry of Trade, Industry & Energy, Republic of Korea. S.H.B also discloses support for the research of this work from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2024-00405818). This work was supported by the Technology Innovation Program (RS-2024-00434908, Development of a wearable light irradiation device for active drug release and wound treatment using stretchable light-emitting devices) funded By the Ministry of Trade Industry & Energy (MOTIE, Korea). This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2025-25432139). J.W.B. declares no relevant funding.
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Park, H.S., Im, GB., Jeong, S.Y. et al. Nanoparticle-enabled tuning of cell density for enhanced adhesion and tissue repair. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72803-z
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DOI: https://doi.org/10.1038/s41467-026-72803-z
