Manganese doped nanosystem for degrading neutrophil extracellular traps and improving chemotherapy efficiency to synergistically inhibit lung metastasis of breast cancer

•The nanosystem can accumulate at the site of tumor, and also be captured by NETs.•The manganese doped nanosystem could increase the DNase-1 activity efficiently.•The combination of DNase-1 and DOX potently suppressed tumor growth and metastases. New treatment patterns have emerged by destroying neutrophil extracellular traps (NETs) with DNase-1 to prevent tumor metastasis. However, the DNase-1 as a therapeutic agent has short half-life in blood plasma and low potency to kill tumor owing to the intrinsically intricate tumor microenvironment. Herein, a manganese-enriched nanosystem (DMMnSiO3-PEG/DOX/DNase-1) has been developed to inhibit lung metastasis of breast cancer by delivering doxorubicin and DNase-1 for degrading neutrophil extracellular traps and improving chemotherapy therapy synergistically. Specifically, this PEG-modified nanosystem can not only accumulate at the site of tumor tissue but also be captured by NETs. In tumor site, DOX were released from this nanosystem in response to a lower pH and higher GSH to facilitate apoptosis effect of tumor cells efficiently with the help of DNase-1. Then, those remaining nanoparticles were captured by NETs to disassemble them and the released Mn2+ as the cofactor of DNase-1 could increase the NETs lyse. In all, that nanosystem has been proven to inhibit tumor growth by a chemotherapeutic effect and suppresses distant metastasis by disassembling NETs through in vitro and in vivo evaluations. This strategy demonstrates immense potential to provide an effective and safe therapeutic regimen for the treatment in patients with metastatic breast cancer.