Tumor microenvironment-activatable boolean logic supramolecular nanotheranostics based on a pillar[6]arene for tumor hypoxia imaging and multimodal synergistic therapy

Supramolecular construction of nanotheranostics is a highly challenging and demanding task for tumor precision diagnosis and therapy. In this study, inspired by specific microenvironments and the abnormal metabolic path of tumors, we skillfully integrated hypoxia-responsive fluorescence imaging, cancer starvation therapy, oxidative therapy, and chemotherapy to fabricate supramolecular nanotheranostics (GOx@NPs) through host-guest interactions between a carboxylated-pillar[6]arene (WP6) host and a prodrug guest (Azo-G). Depending on the excellent responsive ability to hypoxia, esterase and pH which are signature features of the tumor microenvironment, GOx@NPs could not only realize selective fluorescence imaging and diagnosis against tumor hypoxia but also possess remarkable synergistic treatment effects of starving therapy, oxidative therapy, and chemotherapy on cancer cells in vitro and in vivo. Furthermore, we developed a two-layer cascade logic gate based on GOx@NPs to perform intracellular logic operations with cancer endogenous inputs for biocomputing. This study provides a referential example to develop intelligent tumor microenvironment-responsive supramolecular nanosystems with the ability of logical computing for precision cancer diagnosis and synergistic therapy.