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Peer-reviewedCC BY 4.0Journal of the American Chemical Society

G‑Quadruplex-Interacting Photooxidative Platinum(IV) Prodrug for Inhibiting Oncogene Transcription and Amplifying Antitumor Immunity

  • Dengshuai Wei1,2
  • Yijia Chen1,3
  • Jiaqian Xu1,3
  • Guangyu Zhu1,3
  1. 1Department of Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong SAR 999077, P. R. China
  2. 2Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, P. R. China
  3. 3City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, P. R. China
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Abstract

Conventional platinum (Pt)-based chemotherapeutics elicit cancer cell death primarily through DNA binding, but this approach is inherently limited by poor site specificity and a lack of spatiotemporal control, which compromises therapeutic precision and safety. To overcome these limitations, we report DNATplatin, an in situ activatable and photooxidative Pt­(IV) prodrug designed to combine precise recognition of DNA secondary structures with targeted genetic intervention through DNA photooxidation. By incorporating a bis-N-methylpyridinium moiety to selectively recognize DNA, DNATplatin shows a 10-fold increase in the levels in genomic DNA relative to oxaliplatin and a 2.5-fold emission turn-on selectivity for G-quadruplexes (G4s) over typical duplex DNA. Following precise nuclear localization, photoactivated DNATplatin acts as a potent photooxidant that oxidizes G4, dismantles G4 scaffolds, and abrogates circular dichroism signatures. These orchestrated lesions generate localized oxidative stress and selectively silence major G4-driven oncogenes, thereby effectively circumventing traditional Pt resistance by bypassing canonical adduct-dependent pathways. In a murine triple-negative breast tumor model, DNATplatin produces profound tumor suppression and elicits a robust systemic immune response, characterized by CD4+/CD8+ T-cell activation and depletion of Foxp3+ regulatory T cells. Collectively, this work establishes a controllable “target-and-destroy” strategy and underscores the potential of Pt­(IV) photooxidants for topology-selective genetic intervention.

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Cite

BibTeXRIS
BibTeX
@article{wei2026gquadruplexinteracting,
  title = {{G‑Quadruplex-Interacting Photooxidative Platinum(IV) Prodrug for Inhibiting Oncogene Transcription and Amplifying Antitumor Immunity}},
  author = {Dengshuai Wei and Yijia Chen and Jiaqian Xu and Guangyu Zhu},
  journal = {Journal of the American Chemical Society},
  year = {2026},
  month = oct,
  doi = {10.1021/jacs.6c16762},
  url = {https://doi.org/10.1021/jacs.6c16762},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - G‑Quadruplex-Interacting Photooxidative Platinum(IV) Prodrug for Inhibiting Oncogene Transcription and Amplifying Antitumor Immunity
AU  - Dengshuai Wei
AU  - Yijia Chen
AU  - Jiaqian Xu
AU  - Guangyu Zhu
PY  - 2026
DA  - 2026/10/21
JO  - Journal of the American Chemical Society
DO  - 10.1021/jacs.6c16762
UR  - https://doi.org/10.1021/jacs.6c16762
AB  - Conventional platinum (Pt)-based chemotherapeutics elicit cancer cell death primarily through DNA binding, but this approach is inherently limited by poor site specificity and a lack of spatiotemporal control, which compromises therapeutic precision and safety. To overcome these limitations, we report DNATplatin, an in situ activatable and photooxidative Pt­(IV) prodrug designed to combine precise recognition of DNA secondary structures with targeted genetic intervention through DNA photooxidation. By incorporating a bis-N-methylpyridinium moiety to selectively recognize DNA, DNATplatin shows a 10-fold increase in the levels in genomic DNA relative to oxaliplatin and a 2.5-fold emission turn-on selectivity for G-quadruplexes (G4s) over typical duplex DNA. Following precise nuclear localization, photoactivated DNATplatin acts as a potent photooxidant that oxidizes G4, dismantles G4 scaffolds, and abrogates circular dichroism signatures. These orchestrated lesions generate localized oxidative stress and selectively silence major G4-driven oncogenes, thereby effectively circumventing traditional Pt resistance by bypassing canonical adduct-dependent pathways. In a murine triple-negative breast tumor model, DNATplatin produces profound tumor suppression and elicits a robust systemic immune response, characterized by CD4+/CD8+ T-cell activation and depletion of Foxp3+ regulatory T cells. Collectively, this work establishes a controllable “target-and-destroy” strategy and underscores the potential of Pt­(IV) photooxidants for topology-selective genetic intervention.
SN  - 0002-7863
SN  - 1520-5126
ER  -