Aggregation-Induced Photosensitization of Long-Chain-Substituted Osmium Complexes for Lysosomes Targeting Photodynamic Therapy

Photodynamic therapy (PDT) has been demonstrated to be an effective tool for cancer treatment. Seeking organelle-targeting photosensitizers (PSs) with robust reactive oxygen species (ROS) production is extremely in demand. Herein, we propose an aggregation-induced photosensitization strategy for effective PDT with osmium complexes. We designed and synthesized three osmium complexes (<b>Os-Me</b>, <b>Os-tBu</b>, and <b>Os-Nonly</b>) with ligands of different alkyl chains. In phosphate-buffered saline solution, the complex <b>Os-Nonly</b> formed a spherical aggregate with diameters of around 220 nm. The results from ROS assays indicate that <b>Os-Nonly</b> showed the highest efficiency in generating superoxide anions and singlet oxygen, demonstrating its role as a type I/II photosensitizer. Additionally, <b>Os-Nonly</b> specifically targeted lysosomes in 4T1 and MCF-7 cells, producing ROS in a sustained and efficient manner with high phototoxicity (IC₅₀ = 6.999 μM in MCF-7 cells), thereby inducing cancer cell death. In 4T1-tumor-bearing mice models, <b>Os-Nonly</b> effectively inhibited tumor growth with a minimal impact on normal organs.