In Situ Nitric Oxide Gas Nanogenerator Reprograms Glioma Immunosuppressive Microenvironment

Universal chemotherapy in glioblastoma patients causes chemoresistance and further limits immune cells by creating an immunosuppressive tumor microenvironment that are difficult to solve by single-drug therapeutic approaches. Here, this work designs hybrid drug-loaded nanoliposomes by co-loading the chemotherapeutic drug temozolomide (TMZ) and nitric oxide (NO) prodrug JS-K with sphingosine-1-phosphate molecules (S1P) on the surface. The S1P-S1P receptors axis endows nanoliposomes with rapid targeting and lysosomal escaping capability. Then, fine-tuned TMZ release and NO gas production following JS-K release in glioma microenvironment decrease chemoresistance and increase tumor immunogenicity through inhibiting the cellular autophagy as well as inducing mitochondrial dysfunction. RNA sequencing analysis demonstrates that the NO gas generation reprograms glioma microenvironment immune and inflammation-related pathways. The positive immune response in turn effectively activates the enhanced efficacy of chemotherapy. NO gas generated nanoliposomes thus have attractive paradigm-shifting applications in the treatment of cold tumors across a range of immunosuppressive indications.

Automated summary

This study designs hybrid drug-loaded nanoliposomes to address the issues of multi-drug resistance and tumor microenvironment immunosuppression in glioblastoma patients. By co-loading TMZ, NO prodrug JS-K, and S1P molecules on the surface, the nanoliposomes exhibit rapid targeting and lysosomal escaping capabilities. Fine-tuned release of TMZ and generation of NO gas in the glioma microenvironment decrease chemoresistance and increase tumor immunogenicity. RNA sequencing analysis demonstrates that NO gas generation reprograms immune and inflammation-related pathways in the glioma microenvironment, effectively enhancing the efficacy of chemotherapy. Therefore, NO gas generated nanoliposomes have promising applications in the treatment of immunosuppressive diseases.