Smart Interactive System for the Enhanced Bioimaging and Multi‐Drug Synergistic Therapy in Tumor‐Microenvironment

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Tumor microenvironment (TME) interactive platforms are promising for accurate diagnostics and therapeutics. Herein, a smart interactive system (G⊂H) consisting of a hypoxia‐acid dual triggered multifunctional guest (G) and an amphipathic metal‐organic capsule (H) was successfully established for bioimaging and treatment. Hydrophobic G is encapsulated in cavity of H to form the homogeneous soluble G⊂H, which enhances its accumulation in tumor cells, controls the interactive regulation between G⊂H and TME, and facilitates the sensitivity of tumor cell therapy. When triggered in TME, G⊂H selectively releases an alkylating agent and a doxifluridine (DFUR) via the activation of azo and ketal linkers for multidrug chemotherapy, and the fluorescence emission from the activated G⊂H is used for real‐time release visualization of the hypoxia‐activating drug in cell substructure and hypoxia imaging. Owing to its homogeneous delivery, TME regulation and TME response properties toward the hypoxia tumor cells, G⊂H exhibits significantly higher toxicity in a hypoxic environment (0.1% O 2 ) than that in normoxia. As expected, G⊂H performs good imaging capability and treatment effect in hypoxia tumor cells, flow cytometry assay and tumor‐bearing mice, implying its great potential in bioimaging and multidrug synergistic therapy.