Construction Of NanoDNAzyme-MnO₂ Using Functionalized DNA As A Template To Inhibit Tumor Metastasis

Cancer,which is drawing much attention of many scholars around the world to solve,is one of the main killers that threaten human health.With the development of cancer research,we found that the fatal risk of cancers is that they will invade other normal organs and even spread all over the body after a certain period of growth.Tumor metastasis is a complex process,which involve many factors.Studies have revealed that epithelial-mesenchymal transformation(EMT)is a key step to promote tumor metastasis.Under the regulation of many factors and environment,epithelioid cells can undergo bidirectional changes with mesenchymal cells,thus enhancing the invasion and metastasis of tumor cells.As one of the potential targets,Twist1 transcription factor is frequently overexpressed in invasive breast cancer for EMT.Therefore,gene therapy could be used to inhibit EMT using DNAzyme,which works as a gene silencing tool with low price,simple synthesis,good stability and easy modification.However,because DNAzyme is easily degraded by nuclease in vivo,it is necessary to design appropriate nanocarriers to deliver it to the target site safely.Therefore,Twist1 targeted DNAzyme was used as biological template to prepare Dz-MnO₂ nanocomplex for chemodynamic and gene dual-mode therapy.In this system,Twist1 target DNAzyme complementary single stranded DNA was used as template for the preparation of Twist1-DNAzyme long single stranded DNA containing multiple repeated units by RCA technology.Then the Dz-MnO₂ nanocomplex would be prepared using the long single stranded DNA as a biological template.The nanocomplex protects DNAzyme from degradation by nuclease in vivo and effectively delivers it to target cells.When Dz-MnO₂ nanocomplex is internalized by cancer cells,it can be degraded by GSH,as well as react with excess intracellular H₂O₂ to releaseO₂ to relieve hypoxia.The resulting Mn²⁺can further react with H₂O₂ to release·OH to kill tumor cells.Meanwhile,the Mn²⁺can also works as the cofactor of the released Twist1-DNAzyme for effectively cleaving Twist1m RNA.In addition,Mn²⁺can transform pro-tumor type M2 macrophages in the immune microenvironment into anti-tumor type M1 macrophages and improve the immune microenvironment to assist the cancer therapy.In vivo and in vitro experiments have demonstrated that the nanomaterial can inhibit tumor growth and metastasis effectively through CDT therapy combining with gene therapy.This combination therapy can effectively inhibit the metastasis of triple negative breast cancer and will provide new ideas and methods for the treatment of triple negative breast cancer.