A Dual‐Locking G‐Quadruplex DNA Targeting Strategy Based on a Tumor‐Accumulating Porphyrin‐Ruthenium(II) Conjugate for Type I Photodynamic Therapy

ABSTRACT The hypoxic tumor microenvironment severely limits the effectiveness of photodynamic therapy (PDT) in hepatocellular carcinoma (HCC). To overcome this limitation, we designed and synthesized a dual‐functional photosensitizer, PorRu, by conjugating a porphyrin unit with a ruthenium(II) polypyridyl complex through a flexible alkyl chain. PorRu is engineered to achieve specific accumulation in HCC cells and “dual‐lock” binding with G‐quadruplex DNA (G4 DNA). It demonstrated approximately 3–6 folds higher photocytotoxicity against HCC cells compared to its individual components, owing to enhanced tumor targeting and improved Type I photochemical reactivity. Unlike conventional oxygen‐dependent PDT, PorRu efficiently generates reactive oxygen species (ROS) under near‐infrared irradiation, directly oxidizing guanine bases in G4 DNA and causing extensive oxidative damage under both normoxic and hypoxic conditions. The ROS burst induces severe oxidative stress, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA), ultimately activating the inflammasome and triggering pyroptosis. In vivo studies validated the potent tumor‐suppressive capability of PorRu, highlighting its potential to circumvent hypoxia‐induced therapy resistance. This work not only presents PorRu as a promising agent for precise HCC targeting but also offers a novel strategy to enhance PDT efficacy against hypoxic tumors.