π-Extended Ru–COUBPY Photosensitizers for <i>In Vivo</i> Anticancer Phototherapy Using One-Photon 780 nm Near-Infrared Light

Photodynamic therapy (PDT) is a promising cancer treatment modality, offering precise spatial and temporal control of drug activation using light. However, clinical translation of current photosensitizers (PSs) is limited by inefficient activation at wavelengths within the phototherapeutic window, especially in the deep-red and near-infrared (NIR) region. NIR light provides advantages such as reduced absorption by endogenous chromophores, minimized tissue photodamage, and improved tissue penetration, highlighting the need for PSs to be activatable in this range. Herein, we report a novel series of ruthenium(II) polypyridyl complexes (<b>Ru4-7</b>) featuring π-extended COUBPY ligands, designed <i>via</i> a vinylogation strategy and synthesized through an innovative postcoordination ligand assembly approach. This structural modification enhances molar absorptivity and red-shifts the absorption bands well into the NIR region without substantially compromising photostability. Complexes <b>Ru4-7</b> efficiently generate both Type I and Type II reactive oxygen species, and their photodynamic activity, combined with preferential mitochondrial accumulation, leads to potent nanomolar phototoxicity against CT-26 colorectal cancer cells under deep-red and NIR irradiation, even under hypoxia. Notably, the lead complex <b>Ru6</b> demonstrated strong <i>in vivo</i> phototoxicity in mice bearing subcutaneous CT-26 tumors, achieving significant tumor growth inhibition upon irradiation with 660 and 780 nm light. <b>Ru6</b> thus represents one of the first Ru(II) polypyridyl complexes to exhibit robust <i>in vivo</i> PDT antitumor activity under one-photon NIR activation. Its broad wavelength activation profile further underscores its potential versatility for treating tumors of varying size and anatomical location depending on specific light penetration requirements. These findings mark a promising step toward next-generation PSs for treating deep-seated and hypoxic tumors.