Polypyridyl Ruthenium(II) Complexes Functionalized with Fatty Acids for Photodynamic Therapy and Induction of Pyroptosis

To address the challenges associated with low cellular uptake efficiency of metal-based anticancer agents and the suboptimal therapeutic efficacy of photodynamic therapy (PDT), a series of polypyridyl ruthenium(II) complexes (Ru Cn) with tunable carbon chain lengths were rationally designed and synthesized through the incorporation of fatty acid moieties, which confer enhanced lipid solubility and membrane-targeting capabilities. Among these, the octadecanoic acid-modified ruthenium complex (Ru-C18) exhibited superior anticancer activity. Cytotoxicity assays demonstrated that Ru-C18 displayed sub-molar cytotoxic potency under light irradiation. Co-localization studies confirmed its preferential accumulation in lysosomes after cellular internalization. Upon light activation, Ru-C18 efficiently generated singlet oxygen and induced hallmark features of pyroptosis, including plasma membrane blebbing, cellular swelling, and Gasdermin-dependent membrane pore formation. Consequently, Ru-C18 significantly suppressed tumor cell proliferation via activation of the pyroptotic pathway. These findings offer new insights into the rational design of highly effective and selectively targeted photodynamic anticancer agents.