Supramolecular nanovesicles for synergistic glucose starvation and hypoxia-activated gene therapy of cancer

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.

Automated summary

Glucose starvation has been used as a therapeutic strategy to inhibit tumor growth by regulating glucose metabolism, but the hypoxic tumor microenvironment can limit its efficacy. This study developed a dual-lock supramolecular nanomedicine system for synergistic cancer therapy, integrating glucose oxidase-induced starvation and hypoxia-activated gene therapy. The system showed integrated therapeutic effects in vitro and in vivo for tumor suppression, through the controlled release of glucose oxidase and activation of the therapeutic gene in response to cancer-specific reactive oxygen species.