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Title: Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness
Authors: Chen, X 
Fan, Y 
Sun, J 
Zhang, Z 
Xin, Y 
Li, K 
Tang, K 
Du, P 
Liu, Y
Wang, G
Yang, M 
Tan, Y 
Issue Date: Nov-2021
Source: Acta Biomaterialia, Nov. 2021, v. 135, p. 493-505
Abstract: As the driving force of tumor progression, cancer stem cells (CSCs) hold much lower cellular stiffness than bulk tumor cells across many cancer types. However, it remains unclear whether low cell stiffness can be harnessed in nanoparticle-based therapeutics for CSC targeting. We report that breast CSCs exhibit much lower stiffness but considerably higher uptake of nitrogen-doped graphene quantum dots (N-GQDs) than bulk tumor cells. Softening/stiffening cells enhances/suppresses nanoparticle uptake through activating/inhibiting clathrin- and caveolae-mediated endocytosis, suggesting that low cell stiffness mediates the elevated uptake in soft CSCs that may lead to the specific elimination. Further, soft CSCs enhance drug release, cellular retention, and nuclear accumulation of drug-loaded N-GQDs by reducing intracellular pH and exocytosis. Remarkably, drug-loaded N-GQDs specifically eliminate soft CSCs both in vitro and in vivo, inhibit tumor but not animal growth, and reduce the tumorigenicity of xenograft cells. Our findings unveil a new mechanism by which low cellular stiffness can be harnessed in nanoparticle-based strategies for specific CSC elimination, opening a new paradigm of cancer mechanomedicine.
Keywords: Cellular stiffness
Cancer stem cell
Cellular uptake
Publisher: Elsevier
Journal: Acta biomaterialia 
EISSN: 1742-7061
DOI: 10.1016/j.actbio.2021.08.053
Rights: © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
The following publication Chen, X., Fan, Y., Sun, J., Zhang, Z., Xin, Y., Li, K., Tang, K., Du, P., Liu, Y., Wang, G., Yang, M., & Tan, Y. (2021). Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness. Acta Biomaterialia, 135, 493-505 is available at
© 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
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