Construction Of Nano Drug Co-delivery System And Multi-route Antitumor Activity Reasearch

At present,cancer is still one of the major diseases that seriously threaten human’s health.Traditional treatments of cancer such as chemotherapy,surgery and radiotherapy have shown their abilities in the inhibition of cancer growth,but they are vulnerable to metastasis and relapse after treatment,which are the main reasons for the high tumor mortality rate.In the latest research progress,immunotherapy has shown that the patient’s own immune system can be used to eradicate tumors.Tumor treatment can be achieved by genetically programming T cells to specifically recognize tumor cells.For immunotherapy to work efficiently,tumors should be highly immunogenic（hot）.Unfortunately,the majority of human tumors are hypoimmunogenic（cold）,which makes the current immunotherapy are only successfully applied to a few types of cancers,such as including melanoma,leukemia,and lung carcinoma.Pyroptosis,which is a type of programmed cell death,provides a new window to relieve the immunosuppression of tumor microenvironment and promote a systemic immune response in the treatment of tumors.However,the key protein gasdermin during the caspase-1-mediated pyroptosis process is low-expression in most tumor cells.In addition,new inorganic nano-materials can also be used in biomedical applications such as bio-imaging,drug delivery,antibacterial and tumor treatment due to their unique properties.Molybdenum disulfide has the characteristics of large specific surface area,excellent photothermal performance and stability,which has shown great potential in the medical field and has been widely concerned by researchers in recent years.Based on the above background,we have successfully constructed a self-assembled nano-system（Nig+DAC）@Hm A of hexahistidine（His₆）-metal assembly（Hm A）nano-carrier to co-deliver nigericin（Nig）and 5-aza-2’-deoxycytidine（DAC）for cancer cell pyroptosis and tumor immunotherapy.Molybdenum disulfide nanosheets loaded with siRNA can act on tumors through photothermal therapy and gene silencing to achieve the therapeutic effect of tumors.The details are as follows:（1）Nig induces the nucleotide-binding oligomerization domain-like receptor protein 3（NLRP3）inflammasome and caspase-1 proteins activation;DAC up-regulates gasdermin D（GSDMD）expression by inhibiting DNA methylation.We have constructed a self-assembled nano-system of hexahistidine（His₆）-metal assembly（Hm A）nano-carrier to transport Nig and DAC into the tumor tissue.The results show that the inflammation-activated caspase-1 protein by Nig further successfully cleavage the overexpressed GSDMD protein by DAC,effectively inducing cancer cell pyroptosis.This nanosystem-mediated cell pyroptosis can successfully activate immune cells to inhibit the growth of tumors and realize the immunotherapy of tumors with no obvious side effects in vivo.（2）Molybdenum disulfide nanosheets have photothermal performance,which can rapidly heat up under the irradiation of nano laser.Because tumor cells have high expression of PD-L1,which binds to PD-1 on the surface of T lymphocytes.PD-L1 siRNA can bind to the m RNA expressing PD-L1 in cells to precisely silence the expression of PD-L1,and T cells are thus inhibited.Therefore,we synthesized molybdenum disulfide nanosheets by Hydrothermal method,and then successfully loaded PD-L1siRNA on molybdenum disulfide nanosheets.Using the photothermal properties of molybdenum disulfide,the tumor can be transformed from a"cold tumor"to a"hot tumor"under the irradiation of 1064 nm laser.Photothermal treatment of the tumor was thus realized.In addition,the gene silencing ability of the loaded PD-L1 siRNA is used to reduce the expression of PD-L1 on the surface of tumor cells to achieve the photothermal/gene synergistic anti-tumor effect.