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CXCR4 Clustering Induced by Polymeric Nanothreads Impedes Cancer Cell Metastasis via PIEZO1-Mediated

Junzhu Shi1, Chendong Liu1, Jiaqi Liu1

  • 1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China.

Advanced Healthcare Materials
|June 26, 2025
PubMed

Insights

Polymeric nanothreads enhance antagonism by clustering CXC chemokine receptor 4 (CXCR4). This process activates the mechanosensitive ion channel PIEZO1, crucial for blocking cancer cell metastasis.

Area of Science:

  • Biophysics
  • Cell Biology
  • Nanomedicine

Background:

  • Antagonist binding to target molecules influences downstream pathways.
  • Polymeric nanothreads form cell-surface patches that induce CXC chemokine receptor 4 (CXCR4) clustering for enhanced antagonism.
  • The mechanism behind this enhanced antagonism is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of nanothread-induced CXCR4 clustering and antagonism.
  • To investigate the role of mechanosensitive ion channels in this process.
  • To determine if PIEZO1 activation is essential for nanothread-mediated CXCR4 antagonism.

Main Methods:

  • Utilized polymeric nanothreads to induce CXCR4 clustering on cell surfaces.
  • Investigated F-actin rearrangement and mechanical stress generation.
  • Assessed the impact of PIEZO1 inhibition on CXCR4 antagonism and downstream effects.
  • Evaluated effects on epithelial-to-mesenchymal transition and cancer metastasis in vitro and in vivo.

Main Results:

  • Nanothread patching triggers F-actin rearrangement and mechanical stress, activating PIEZO1.
  • PIEZO1 activation is critical for the enhanced CXCR4 antagonism mediated by nanothread patching.
  • Inhibiting PIEZO1 significantly reduces the nanothread's antagonistic effect.
  • PIEZO1 inhibition attenuated the suppression of cancer cell epithelial-to-mesenchymal transition and metastasis.

Conclusions:

  • PIEZO1-mediated mechanotransduction is a key mechanism amplifying CXCR4 antagonism.
  • Nanothread-induced receptor clustering and PIEZO1 activation offer a novel strategy for cancer therapy.
  • Targeting mechanotransduction pathways alongside receptor antagonism presents a promising therapeutic approach.
Keywords:
CXCR4 antagonismPIEZO1cell metastasismechanotransductionreceptor clustering

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