Targeting delivery of CRISPR systems into tumours to edit glutamine metabolism for cancer therapy by DPA-Zn-modified nanoparticles†

Tumour cells exhibit distinct metabolism to sustain their proliferation and survival, making targeting metabolic pathways an appealing option for tumour therapy. Glutamine metabolism plays a crucial role in fuelling tumour growth and modulating the tumour microenvironment. However, the clinical translation of glutamine metabolism-targeting therapies faces poor efficiency and systemic toxic effects. Here, we constructed biocompatible and functional polymer nanoparticles to deliver CRISPR-Cas9 into tumours for efficient and simultaneous gene editing, which can cut off two genes that express glutaminase (GLS1) and phosphoribosyl pyrophosphate amidotransferase (PPAT) to manipulate glutamine metabolism. The results demonstrated that genetic manipulation of glutamine metabolism significantly inhibited tumour development and metastasis while also favourably altering the tumour microenvironment. Importantly, this method improved antitumour immunity and promoted long-term immunological memory. This work highlights the potential of simultaneously targeting multiple glutamine metabolic pathways through gene editing, providing a promising strategy for cancer therapy.