Glucose starvation has emerged as a therapeutic strategy to inhibit
tumor growth by regulating
glucose metabolism. However, the rapid proliferation of
cancer cells could induce the hypoxic tumor microenvironment (TME) which limits the therapeutic efficacy of
glucose starvation by vascular isomerization. Herein, we developed a "dual-lock" supramolecular nanomedicine system for synergistic
cancer therapy by integrating
glucose oxidase (GOx) induced
starvation and
hypoxia-activated gene therapy. The host-guest interactions (that mediate nano-assembly formation) and
hypoxia-activatable promoters act as two locks to keep
glucose oxidase (GOx) and a therapeutic plasmid (RTP801::p53) inside supramolecular
gold nanovesicles (Au NVs). Upon initial dissociation of the host-guest interactions and hence Au NVs by
cancer-specific
reactive oxygen species (ROS), GOx is released to consume
glucose and
oxygen, generate H2O2 and induce the hypoxic TME, which act as the two keys for triggering burst payload release and promoter activation, thus allowing synergistic
starvation and gene therapy of
cancer. This "dual-lock" supramolecular nanomedicine exhibited integrated
therapeutic effects in vitro and in vivo for
tumor suppression.