Zeolitic imidazolate framework-based nanoparticles for the cascade enhancement of cancer chemodynamic therapy by targeting glutamine metabolism

The reprogrammed amino acid metabolism maintains the powerful antioxidant defense and DNA damage repair capacity of cancer cells, which could promote their escape from reactive oxygen species (ROS)-induced damage and inevitably diminish the efficacy of ROS-based therapies. Herein, we propose a strategy to enhance the effect of chemodynamic therapy (CDT) via glutaminolysis-targeted inhibition for cancer cells dependent on abnormal glutamine metabolism. To screen optimum drugs targeting glutamine metabolism, transcriptomic analysis is performed to identify predictive biomarkers. Eventually, telaglenastat (CB-839) is used to block mitochondrial glutaminase 1 (GLS 1) in basal-like breast cancer and loaded into the developed iron-doped zeolitic imidazolate frameworks (ZIF(Fe) NPs) to form ZIF(Fe)&CB nanoparticles, which are able to co-deliver Fe2+ and CB-839 into the tumor. CB-839 induced-glutaminolysis inhibition not only reduces intracellular antioxidants (glutathione, taurine) to amplify Fe2+-induced oxidative stress, but also decreases nucleotide pools (e.g., adenosine, dihydroorotate) to incur the deficiency of building blocks for DNA damage repair, thereby promoting the cell-killing effect of CDT. In vivo assessments further confirm the enhanced anticancer performance and good biocompatibility of ZIF(Fe)&CB nanoparticles. This study provides a promising strategy for the development and improvement of ROS-based anticancer nanosystems.