Nanoparticulate Cationic Poly(amino acid)s Block Cancer Metastases by Destructing Neutrophil Extracellular Traps

Cancer metastasis that is resistant to conventional therapies has become a major cause of patient death. Recent reports indicate that the neutrophil extracellular trap (NET) is closely associated with cancer distant metastases, and the cell-free DNA of NETs has been identified as the ligand of the transmembrane protein CCDC25 of cancer cells, acting as a chemokine to induce cancer cell migration to distant organs. In this work, we present the poly(aspartic acid) based-cationic materials to interfere with the interaction between NET-DNA and CCDC25, and furthermore to inhibit NET-DNA-mediated cancer cell chemotaxis and migration. Because of a stronger binding affinity to DNA and favorable retention in the liver, nanoparticulate poly(aspartic acid) derivatives (cANP) efficiently reduce the level of hepatic NET-DNA infiltration, leading to a significant suppression of cancer metastases in mice and several human metastatic models. Moreover, the cANP exhibits no toxicity to organs of animals during the entire treatment. Thus, this work suggests a strategy for controlling cancer metastases, which will benefit patients in clinics.

Automated summary

Cancer metastasis that is resistant to conventional therapies has become a major cause of patient death. Recent reports indicate that the neutrophil extracellular trap (NET) is closely associated with cancer distant metastases, and the cell-free DNA of NETs has been identified as the ligand of the transmembrane protein CCDC25 of cancer cells, acting as a chemokine to induce cancer cell migration to distant organs. A strategy using poly(aspartic acid) based-cationic materials is presented to interfere with the interaction between NET-DNA and CCDC25, inhibiting NET-DNA-mediated cancer cell chemotaxis and migration. Nanoparticulate poly(aspartic acid) derivatives efficiently reduce hepatic NET-DNA infiltration and suppress cancer metastases in mice and human metastatic models without toxicity to organs.