Ruthenium (II)‐Coordinated Supramolecular Metallodrug Complex Realizing Oxygen Self‐Supply In Situ for Overcoming Hypoxic Tumors

Abstract Tumor hypoxia greatly limits the antitumor therapeutic efficacy of oxygen (O₂)‐dependent treatments. The common strategies of doping O₂ generating compounds into one “package” may lead to insufficient O₂ supply in situ in cancer cells due to the relatively low loading content, limited reproducibility, and uncontrollable release kinetics. Herein, organometallic drug complexes combined with a supramolecular interaction strategy are proposed to realize a stable and efficient O₂ self‐supply in situ for overcoming hypoxic tumors. A ruthenium (II)‐coordinated supramolecular metallodrug complex (RuSMDC) is first designed and synthesized via host–guest interactions between two functionalized drug molecules, in which ruthenium is used to catalyze the decomposition of hydrogen peroxide to produce O₂. The obtained RuSMDC further self‐assembles into Ru‐containing supramolecular metallodrug micelles (RuSMDMs), which provides sufficient O₂ for chemotherapy and photodynamic therapy (PDT) oncotherapy in an anaerobic tumor environment. In vitro and in vivo studies further confirm that RuSMDMs effectively alleviate the tumor hypoxic environment, greatly improve the therapeutic effect of chemotherapy and PDT oncotherapy, and reduce the systemic toxicity to normal organs.