Recent advances in dual-function fluorescent ligands targeting mitochondrial DNA G-Quadruplexes for Cancer...

The identification of G-quadruplex (G4) structures in mitochondrial DNA (mtDNA) offers a promising avenue for targeted cancer therapy. Unlike nuclear DNA, mtDNA lacks histone protection and comprehensive repair mechanisms, making mitochondrial G4s (mtG4s) highly vulnerable pharmacological targets. This review systematically examines recent advancements in mtG4-targeted dual-function fluorescent ligands from our group and others, which integrate in situ fluorescence visualization with precise therapeutic intervention. We dissect their core design principles, structure-activity relationships, and categorize them into two paradigms: traditional steric hindrance-based ligands and photodynamic therapy (PDT)-active ligands. Furthermore, we critically evaluate their pharmacological mechanisms, highlighting their robust ability to induce mitochondrial metabolic collapse, activate innate immune regulatory pathways (e.g., cGAS-STING), and trigger multifaceted programmed cell death networks (e.g., PANoptosis, ferroptosis). Finally, we address current challenges in deep-tissue non-linear optical imaging and in vivo pharmacokinetic translation, outlining the future integration of mtG4 theranostics into combinatorial tumor immunotherapy.