Mitochondria-Targeting 1H-Imidazo[4,5-<i>f</i>][1,10]phenanthroline-Based Binuclear Ru(II)/Ir(III)/Re(I) Complexes as a Promising Avenue for <i>In Vitro</i> Genotoxicity and <i>In Vivo</i> Tumor Immunotherapy

Bimetallic complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology. However, the effectiveness of existing therapies remains limited in the treatment of triple-negative breast cancer (MDA-MB-231) and human melanoma cancer (A375). In this study, we introduced mitochondrial-targeting imidazophenanthroline-based binuclear Ru(II)/Ir(III)/Re(I) complexes capable of generating ROS, facilitating mitochondrial dysfunction and oxidative DNA damage, and inducing G0/G1 phase cell cycle arrest. Among all these complexes, the naphthalene-substituted imidazophenanthroline-based bisiridium complex (<b>BNS-2</b>) exhibited the best potency against MDA-MB-231 TNBC and A375 cancer cell lines. Eventually, this complex induced the upregulation of BAX and cleaved caspase-3, downregulated BCL-2, triggered the caspase 3/9 pathway for apoptosis, and shifted the death mechanism from necrosis to apoptosis in tumor cells <i>in vivo</i>. This complex significantly reduced tumor volume and protected the mice against significant weight loss without causing liver or kidney toxicity.