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

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.