A smart small molecule as specific fluorescent probe for sensitive recognition of mitochondrial DNA G-Quadruplexes

G-quadruplex (G4) has become an essential target for the therapy of human genetic diseases (cancer included) with important biological functions for regulation and monitoring. In contrast, little information about G-quadruplexes in mitochondria is known due to the limited development of fluorescent ligands for mitochondrial DNA (mtDNA) G4 detection, urging the design of fluorogenic detection ligands. Herein, we designed and synthesized a robust aggregation-induced emission ligand SPN for recognition of mtDNA G4s, which integrates a G4-active photosensitizer (BZT-triphenylamine) molecule and a mitochondrial targeting functional group (lipophilic triphenylphosphonium cation). Using SPN as the mtDNA G4s sensor, we surprisingly found that SPN could achieve sensitive recognition, sensing, and stabilization of the G4s with the detection limit as low as 0.89 nM. SPN can be highly colocalized with mitochondria, allowing monitoring of mtDNA G4s effectively in vitro. Remarkably, the fluorescence intensity in cancer cells is significantly stronger than that in normal cells, suggesting the potential applications of SPN in cancer diagnosis. This study provides a promising example of designing a fluorescent probe targeting and sensing mtDNA G4s and offers a feasible chemical tool for investigating mtDNA G4s.