Cell Membrane Based Biomimetic Nanoplatform For Tumor Immunotherapy And Synergistic Therapy

The tumor is considered one of the most serious diseases which threaten human public health.In recent years,tumor immunotherapy has been a new therapeutic strategy and has made breakthrough progress.Tumor immunotherapy aims to activate immune cells and modulate the immune system to overcome tumors.Although several immune agents have been used in clinical tumor therapy,it is still hard to extend immune therapy to a wide range of patients owing to many problems,for example,the low infiltration of T cells in the tumor,tumor immune microenvironment restrictions on immune cell function and activity,lack of the expression of the target antigen,etc.These factors limit the number and activity of immune cells involved in tumor therapy.Nanomaterials,with their controllable delivery and flexible modularization,can be reasonably designed to enhance the number of immune cells and regulate the tumor microenvironment,providing an opportunity to safely and effectively promote the clinical transformation of immunotherapy.Cell membrane-based biomimetic nanomaterials are obtained by transforming artificial nanomaterials with biofilm.The biomimetic nanomaterials inherit the complexity of membranes and cell-like functions from the source cells,such as the homologous targeting effect of tumor cells,long circulation and immune escape effect of red blood cells,and non-homologous targeting effect of macrophages to tumor tissues.The cell membrane is rich in protein molecules and tumor antigens,which play an important role in antigen recognition and presentation.In the first chapter,we briefly summarize the cell membrane-based biomimetic nanomaterials and briefly introduce the unique properties of different biomimetic nanomaterials.In the latter part,the problems existing in the current immunotherapy and the advantages of cell membranes-based biomimetic nanomaterials for immunotherapy are summarized.In the second chapter,a multi-functional biomimetic core-shell nanoplatform is designed to improve synergistic chemotherapy and immunotherapy.Oxygen generator catalase(CAT)and doxorubicin(DOX)are embedded in p H-sensitive ZIF-8 to construct the core(ZCD).The membrane of mouse melanoma(B16F10),providing tumor-targeting capabilities and antigens to enhance the immune response,covers the core surface to form a core-shell structure(m ZCD).This oxygen-generating biomimetic core-shell nanoplatform can effectively accumulate in tumors and produce oxygen and down-regulate the expression of hypoxia-inducible factor 1?(HIF-1?),further enhance the therapeutic effect of chemotherapy and reduce the expression of programmed deathligand 1(PD-L1).Combined with immune checkpoint blocking therapy with programmed death 1(PD-1)antibody,dual inhibition of the PD-1/PD-L1 axis elicits significant immune responses and shows significant effects on prolongation of tumor recurrence time and inhibition of tumor metastasis.Therefore,the multifunctional biomimetic nanoplatform provides a potential tumor treatment strategy for synergistic chemotherapy and immunotherapy.In the third chapter,we construct a kind of artificial natural killer cell(a NK).The a NK is emulsified with the erythrocyte membrane(RBCM),perfluorohexane(PFC),and glucose oxidase(GOX).The a NK simulate the two functions of natural killer cells,directly eliminating tumor cells and indirectly killing tumor cells by regulating the immune system.On the one hand,a NK can consume glucose through glucose oxidase and produce hydrogen peroxide to specifically kill tumor cells according to the different tolerance and uptake of a NK in different cells.On the other hand,the produced hydrogen peroxide by a NK can act as a cytokine to cause inflammation,recruit immune cells,and reeducate macrophages to attack tumor cells.PFC is used to carry oxygen for the glucose oxidase catalyzed reaction and normalize the hypoxic tumor microenvironment.This strategy of using simple materials to simulate the function of immune cells could help open up new ideas for biomimetic cellsIn the fourth chapter,a hybrid vesicle system is designed to enhance the innate immune response and then enhance personalized immunotherapy.Bacterial outer membrane vesicles(OMV)deriving from E.coli are hybridized with tumor-derived cell membranes(m T)to form new functional hybrid vesicles(m TOMV).In vitro,the m TOMV could enhance the activation of innate immune cells and the antigen uptake of dendritic cells(DCs),and further increase the specific lysis ability of T cells in homologous tumors.In vivo experiments showed that the m TOMV could be effectively accumulated in the inguinal lymph nodes and inhibit tumor recurrence and lung metastasis.In addition,m TOMV indirectly demonstrated the efficacy of personalized immunotherapy by stimulating innate immune responses to enhance adaptive immunotherapy for homologous tumors rather than heterologous tumors.m TOMV has the function of inhibiting tumor growth also has good biocompatibility and a simple preparation process,so it has a broad clinical application prospect.