Tetrahedral DNA Engineered Mesenchymal Stem Cell Exosomes Relieve Chemotherapy-induced Totoxicity

The incidence and mortality of cancer are increasing year by year,seriously endangering human health.Among the many treatments,chemotherapy is still one of the main methods for clinical treatment of cancer.However,the tumor selectivity of anti-tumor drugs is limited.About less than 10% of the effective drugs can accumulate in tumor tissues while more than60% of the drugs will accumulate in the liver,heart and other normal tissues and organs.Chemical drugs cannot distinguish between normal cells and cancer cells.Therefore,they will also damage normal cells while killing cancer cells.Then the hepatotoxicity and cardiotoxicity caused by anti-tumor therapy eventually cause some cancer patients to die of severe side effects caused by chemotherapy.Recent years,researchers have designed nanoparticle-based drug delivery systems to increase the accumulation of chemotherapeutic drugs in tumor tissues to reduce their side effects.However,half of the drugs still enter normal cells through the circulation,causing serious side effects.Therefore,how to reduce the hepatotoxicity and cardiotoxicity caused by anti-tumor therapy has become the key problem to improve the survival time and quality of life of cancer patients.Some chemotherapeutic drugs,such as doxorubicin(DOX)and cisplatin,can bind to double stranded DNA,inhibit DNA replication in the nucleus and induce apoptosis.The double stranded DNA rich in "G-C" sequence can bind DOX,so it can be used as a scavenger of DOX in normal cells.Here,"the liver and myocardial injury caused by DOX in cancer treatment" is used as a model.By using MSCs-derived exosomes with tissue repair function as a carrier,loaded with tetrahedral DNA(riched in "G-C" sequence that has the function of adsorbing DOX),synthesized a liver and myocardial protective function "Detoxification Repair Agent"-Exo-TDN and PCM-Exo-TDN.First,intravenous injection of "detoxification and repair agent",Exo-TDN mainly enriched in the liver,and it can accumulate in the heart by modifying the myocardial specific targeting peptide PCM.Then inject the chemotherapy drug doxorubicin(DOX),and the DOX that reaches the liver and heart will insert the "G-C" base pair in the Tetrahedral DNA(TDN)part of the "detoxification repair agent",The "detoxification repair agent" combined with DOX is distributed in the cytoplasm,thereby inhibiting DOX from entering the nucleus and achieving the function of protecting cells.At the same time,MSCs-derived exosomes have the function of tissue repair,which can promote cell proliferation and angiogenesis.The results of vitro and vivo experiments show that "detoxification repair agent" has the function of protecting cells and alleviating hepatotoxicity and cardiotoxicity caused by chemotherapeutic drugs.The development of "detoxification repair agent" provides a new idea for solving the side effects of chemotherapy drugs,which is of great significance to prolong the survival period and improve the quality of life of cancer patients.