A Heteroleptic/Trimetallic Os^II–Ru^II–Zn^II Sierpiński Triangle for Efficient Photodynamic Therapy of Hypoxic Tumors Mainly through Type I Mechanism

Owing to its less oxygen-dependent mechanism, type I photodynamic therapy (PDT) has exhibited significant superiority over the more common type II PDT in the treatment of hypoxic tumors. Supramolecular coordination complexes (SCCs) have shown great potential in photodynamic cancer therapy; however, SCC-based photosensitizers which can achieve type I PDT have rarely been reported. Herein, we present the design and synthesis of a novel heteroleptic/trimetallic Os^II-Ru^II-Zn^II Sierpiński triangle ST-2 via coordination-driven self-assembly. The distinctive SCC ST-2 displayed high generation ability of reactive oxygen species (ROS) and boosted the production of O₂^-• involved in the type I mechanism. Detailed in vitro investigations demonstrated ST-2 exhibited excellent PDT efficacy against all tested cancer cell lines with low IC₅₀ values in the subnanomolar range and high phototoxicity indexes (PI) up to 750 even under hypoxic conditions and induced cancer cell death mainly through type I PDT. The anticancer mechanism could be ascribed to the mitochondrial and lysosomal damages as well as cell apoptosis and cell cycle arrest. Further studies confirmed that ST-2 disintegrated 3D multicellular tumor spheroids and effectively inhibited the growth of solid hypoxic tumors in mice with minimal side effects. This work not only provides an alternative strategy for the development of highly efficient type I photosensitizers but also opens new possibilities for Sierpiński triangles in biomedicine.