Cell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition

Minglu Zhou, Chendong Liu, Bo Li, Junlin Li, Ping Zhang, Yuan Huang and Lian Li ()
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Minglu Zhou: Sichuan University
Chendong Liu: Sichuan University
Bo Li: Sichuan University
Junlin Li: Sichuan University
Ping Zhang: Sichuan University
Yuan Huang: Sichuan University
Lian Li: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract The binding of therapeutic antagonists to their receptors often fail to translate into adequate manipulation of downstream pathways. To fix this ‘bug’, here we report a strategy that stitches cell surface ‘patches’ to promote receptor clustering, thereby synchronizing subsequent mechano-transduction. The “patches” are sewn with two interactable nanothreads. In sequence, Nanothread-1 strings together adjacent receptors while presenting decoy receptors. Nanothread-2 then targets these decoys multivalently, intertwining with Nanothread-1 into a coiled-coil supramolecular network. This stepwise actuation clusters an extensive vicinity of receptors, integrating mechano-transduction to disrupt signal transmission. When applied to antagonize chemokine receptors CXCR4 expressed in metastatic breast cancer of female mice, this strategy elicits and consolidates multiple events, including interception of metastatic cascade, reversal of immunosuppression, and potentiation of photodynamic immunotherapy, reducing the metastatic burden. Collectively, our work provides a generalizable tool to spatially rearrange cell-surface receptors to improve therapeutic outcomes.

Date: 2024
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DOI: 10.1038/s41467-024-47111-z

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