The Development Of Bionanomaterials For Novel Cancer Immunotherapy Strategies

Cancer is the second leading cause of death in the industrialized world.Most cancer patients are treated by a combination of surgery,radiation and chemotherapy.Normally,the primary tumor can be efficiently treated by a combination of these standard therapies.However,for the metastatic spread of tumors,these therapies are often not effective.Cancer immunotherapy is reported to kill tumor cells present in the blood circulation and micro-metastases in distant organs via activating the patient’s own immune system.Cancer immunotherapy includes cancer vaccines,immune checkpoint blockade inhibitor therapy and CAR T cell therapy.Though these strategies have achieved some success in clinic for some cancers,some problems such as limited efficacy to some tumors and significant systemic toxicity remain to be solved.Nanomedicines,which are anti-cancer drugs based on bionanomaterials,were originally developed to increase the uptake of chemotherapeutics in tumors and to reduce their systemic toxicity.Nowadays,more and more researches on enhanced cancer immunotherapy based on nanomaterials have been reported.Therefore,we developed a series of novel bionanomaterials based on bionanotechnology,and explored their applications in cancer immunotherapy or its combination with other therapies.Part 1,Chapter 2:Two-dimensional metal-organic-framework as a unique theranostic nano-platform for nuclear imaging and chemo-photodynamic cancer therapy.We developed a novel two-dimensional metal-organic-framework(NMOFs)by bottom up method.Compared to their particulate counterpart,such 2D-NMOFs showed greatly increased drug loading capacity and enhanced light-triggered ROS generation,promising for chemotherapy and photodynamic therapy(PDT),respectively.Meanwhile,our 2DNMOFs could be labeled with a diagnostic radioisotope,99mTc,for single photon emission computer tomography(SPECT)imaging,which indicated efficient tumor accumulation of those 2D-NMOFs upon intravenous injection.While offering a remarkable synergistic in vivo antitumor effect for the combined chemo-PDT,such 2D-NMOFs show efficient biodegradation and rapid renal clearance.Part 2,Chapter 3:Sonodynamic therapy with immune modulatable two-dimensional coordination nanosheets for enhanced anti-tumor immunotherapy.It was found that the synthesized 2D-NMOFs could generate reactive oxygen species(ROS)under ultrasound for sonodynamic therapy.Meanwhile,such Zn-TCPP 2D nanosheets show high loading capacity of oligodeoxynucleotides such as cytosine-phosphorothioate-guanine(CpG),which is a potent toll like receptor 9(TLR9)agonist useful in activating immune responses.Highly effective SDT of primary tumors could release tumor-associated antigens,which working together with Zn-TCPP/CpG adjuvant nanosheets could function like whole-tumor-cell vaccines and trigger tumor-specific immune responses.Interestingly,ultrasound itself could strengthen anti-tumor immune responses by improving the tumor-infiltration of T cells and limiting regulatory T cells in the tumor microenvironment.Thus,SDT using Zn-TCPP/CpG nanosheets after destruction of primary tumors could induce potent antitumor immune responses to inhibit distant abscopal tumors without direct SDT treatment.Moreover,SDT with Zn-TCPP/CpG could trigger strong immunological memory effects to inhibit cancer recurrence after elimination of primary tumors.Part 3,Chapter 4:Non-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and transdermal vaccines.In this system,fluorocarbon modified chitosan(FCS)is optimized as an effective yet biocompatible transdermal carrier to assemble with different proteins including immune checkpoint blockade(ICB)antibodies,antigens,and nuclear acid.The formed FCScontaining nanocomplexes exhibited rather effective transdermal penetration ability via both intercellular and transappendageal routes.Interestingly,non-invasive transdermal delivery of ICB antibodies by FCS induced stronger immune responses to treat mouse melanoma compared to intravenous injection of free antibodies,while presenting reduced systemic toxicity.Moreover,transdermal delivery of SARS-CoV-2 vaccine using FCScontaining nanocomplexes resulted in comparable humoral immunity as well as improved cell immunity and immune memory compared to that achieved with subcutaneous vaccine injection.Thus,FCS-based transdermal delivery system may provide a unique platform for efficient transdermal delivery of biomacromolecules,which showed great potential in clinical application.In conclusion,this dissertation developed a series of new strategies for cancer immunotherapy based on bionanomaterials,and systematically explored the anti-tumor efficacies in different tumor models.The potential of those strategies for clinical translation has been discussed.