Nanoparticle-mediated specific elimination of soft cancer stem cells by targeting low cell stiffness

Xi Chen, Yadi Fan, Jinghua Sun, Zhipeng Zhang, Ying Xin, Keming Li, Kai Tang, Pengyu Du, Yiyao Liu, Guixue Wang, Mo Yang, Youhua Tan (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

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.

Original languageEnglish
Article number34492369
Pages (from-to)493-505
Number of pages13
JournalActa Biomaterialia
Volume135
Issue numberNovember 2021
DOIs
Publication statusPublished - 1 Nov 2021

Keywords

  • cellular stiffness, cancer stem cell, cellular uptake, mechanomedicine, nanoparticle

ASJC Scopus subject areas

  • Engineering(all)

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