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Recent advances in dual-function fluorescent ligands targeting mitochondrial DNA G-Quadruplexes for Cancer
1Nation-Regional Engineering Lab for Synthetic Biology of Medicine, International Cancer Center, School of Pharmacy, Shenzhen University Medical School, Shenzhen 518060, China.
Abstract:
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.
Insights
Mitochondrial G-quadruplexes (mtG4s) are promising cancer targets. New dual-function ligands visualize and treat tumors by inducing cell death and activating immunity, paving the way for advanced cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapy
Background:
- Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) represent novel targets for cancer treatment due to their unique vulnerability.
- mtDNA lacks histone protection and robust repair mechanisms, making mitochondrial G4s (mtG4s) accessible for therapeutic intervention.
Purpose of the Study:
- To review advancements in dual-function fluorescent ligands targeting mtG4s for cancer therapy.
- To analyze the design, mechanisms, and therapeutic potential of these ligands.
Main Methods:
- Systematic review of recent literature on mtG4-targeted ligands.
- Analysis of ligand design principles, structure-activity relationships, and pharmacological mechanisms.
- Evaluation of ligand-induced effects on mitochondrial metabolism, immune pathways, and cell death.
Main Results:
- Dual-function ligands integrate fluorescence visualization with therapeutic action.
- Ligands are categorized into steric hindrance-based and photodynamic therapy (PDT)-active types.
- Effective induction of mitochondrial metabolic collapse, cGAS-STING pathway activation, and PANoptosis/ferroptosis observed.
Conclusions:
- mtG4-targeted ligands show significant potential for cancer therapy by triggering multiple cell death pathways and immune responses.
- Challenges remain in deep-tissue imaging and in vivo translation.
- Future integration of mtG4 theranostics into combinatorial cancer immunotherapy is promising.
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