Dual-targeted Exosomes As Drug Carriers In Response To Tumor Microenvironment For Cancer Immunotherapy

Cancer is one of the leading causes of human death.At present,surgery is the first choice for the treatment of cancer,combined with radiotherapy and chemotherapy.However,these treatment methods often cause unpleasant side effects,and the patients still have a high risk of tumor recurrence.Therefore,it is urgent to develop novel strategies with low side effects and good therapeutic effects on cancer treatment.In recent years,with the advancement of medicine,many new treatment strategies have been developed,such as photothermal therapy,photodynamic therapy,and immunotherapy,which have provided new treatment approaches for cancer patients.Among them,tumor immunotherapy,as an innovative treatment method,has become a hot spot in the field of tumor therapy due to its advantages such as small side effects and long-lasting effects.Immunotherapy is a promising treatment modality and has made remarkable progress in the field of tumor therapy.Tumor immunotherapy is a treatment modality that can fight against tumor by activating the body's immune system,which is different from the previous surgery,chemotherapy and radiotherapy.Under normal circumstances,most tumor cells in the tumor microenvironment can be recognized and killed by the immune system.However,with the development of research,it has been found that tumor can evade the anti-tumor immune response through several mechanisms,making immunotherapy ineffective,and tumor cells can survive.Therefore,the key to improve the treatment is to inhibit tumor immune escape.In response to this problem,some new immunotherapy methods have been developed.Among them,immunotherapy represented by immunocheckpoint inhibitors(ICB)has attracted wide attention.Immune checkpoint is a kind of inhibitory molecule,which plays a protective role in the human immune system.It can prevent autoimmune damage caused by excessive activation of the immune system by suppressing the function of T cells.Among them,the immune checkpoint blockers represented by PD-1/PD-L1 inhibitors and CTLA-4 inhibitors have achieved surprising results in tumor immunotherapy.The results greatly inhibited the immune escape of tumor and made the immune system play a normal role in killing cancer cells.However,the immunotherapy often requires a high concentration of immune checkpoint inhibitors to have a better killing effect on tumor,which leads to the immune-related side effects after treatment in the majority of patients,such as inflammation or autoimmune diseases.In addition,this method has limited systemic antitumor effect on many cancer patients,and due to the systemic delivery,the immunotherapy shows limitations in safety and efficacy.Immunotherapy has been limited by low persistent response rates,low response rates,and immune-related adverse events in clinical environment.Therefore,it is necessary to develop a treatment strategy that can produce an anti-tumor reaction and avoid immune-related side effects.In response to this problem,researchers have used a variety of nanomaterials to load drugs and to impose physical constraints on antibodies,so that low-dose of nanomedicine can produce better therapeutic effects,which provides a potential strategy for improving cancer immunotherapy.Although nanomaterials have made progress in drug delivery,there are still many challenges before using artificial nanoparticles as ideal delivery carriers.For example,nanoparticles have high toxicity,are unstable in the blood and may cause serious side effects,which are difficult to be applied in clinical practice.In addition,the antibody and drug modification process of nanoparticles may affect their activity and have a certain effect on the treatment and targeting effects.Therefore,it is urgent to develop some biomaterials with good biocompatibility and no toxin side effects instead of inorganic nanomaterials as carriers to transport immune drugs to tumor tissues.Exosomes are extracellular vesicles with a size of 40-150 nm released by most cells,which are rich in bioactive molecules such as proteins,lipids,DNA and RNA.In recent years,they have attracted intensive attention in terms of cell-to-cell communication,signal transduction,immune regulation,disease detection and the transmission of bioactive molecules in cells.Exosomes are natural vesicles derived from cells,they have lower toxicity,better tolerance in vivo,low immunogenicity,high biocompatibility and can realize the stable transportation of drugs in blood.It is a highly biocompatible nanocarrier with an internal payload,and shows more flexibility in loading the required antigens to achieve effective delivery.Therefore,exosome-based nanoparticles are promising drug carriers for immunotherapy,which can solve the problems of biocompatibility,potential toxicity and immune response which are difficult to be taken into consideration by traditional drug carriers.However,exosomes-based drug delivery vehicles lack specific targeting capabilities.Therefore,it is of great significance to endow exosomes with a satisfactory targeting ability to improve the delivery performance.In addition,there are few reports on the use of exosomes as delivery carriers for cancer immunotherapy.Based on this,we constructed an exosomal-based drug delivery system and given exosomes with targeted delivery function,and developed a tumor immunotherapy strategy with low toxicity,suppression of immune escape,and enhanced antitumor response.The research contents of this paper are as follows:The first chapter is the introduction.Firstly,we introduces the research progress of tumor treatment,including surgery,radiotherapy,chemotherapy,photodynamic therapy and photothermal therapy.Then,we focuses on the research progress of immunotherapy,including the principle of immunotherapy,the current methods of immunotherapy and the application of nanomaterials as carriers for immunotherapy.Finally,the research progress of exosomes and its application as drug carriers for immunotherapy are described.The second chapter is the study of the drug delivery system based on dual-targeted exosomes for tumor immunotherapy.First of all,we added targeted delivery to exosomes through chemical modification.The functional exosomes are simultaneously labeled with PD-L1 and CD40 ligands.They could not only target tumor cells to prevent tumor immune escape,but also target dendritic cells,and give positive signals to dendritic cells to activate the immune system.At the same time,exosomes were loaded with the drug cGAMP to activate STING signaling pathway,induce dendritic cells to produce interferons,and then activate the anti-tumor immune response in humans.This method shows strong targeting ability to tumor cells and effective activation of the immune system,and the exosomes used as drug carriers have almost no toxic side effects,providing a new strategy for tumor immunotherapy.