Functional Nanobiological Composites For Cancer Immunotherapy

Cancer immunotherapy is a revolutionary method for cancer treatment after traditional surgery,radiotherapy and chemotherapy,which has reformed the mindset from the direct destruction of cancer cells to the rejuvenation of the host's anti-tumor immune response for recognizing and attacking the cells.Many immunomodulators that trigger immune responses have been developed and applied for cancer immunotherapy.However,direct injection of common immunomodulators into the human body is likely to cause excessive immune response,which is very harmful.Therefore,it is of great significance to develop functional immunomodulators that can induce controlled immune response for cancer immunotherapy.Nanotechnology provides a good basis for the development of functional immunomodulators.Compared with traditional nanomedicine,nano drug delivery system has the following advantages in cancer immunotherapy.1)Drugs can be delivered to the needed immune cells and immune tissues,in which nanomaterials are prone to enrichment.2)The nano-drug carriers can be modified to regulate the interaction between nanoparticles and immune cells or organs.3)Nano-drug carrier can improve the pharmacological properties of drugs and further prevent the premature release and degradation of drugs.4)Response-type nano drug carriers can be designed to achieve the specific target ability and reduce off-target toxicity.5)Targeted nanoparticles,combining with controlled and local drug release,can lower the doses of immunocheckpoint inhibitors or activate immunotherapy only at the intended site,thereby reducing the nonspecific security risks associated with immunotherapy.In summary,the development of immunomodulators based on functional nanobiological composites is promising for improving the efficacy of cancer immunotherapy and reducing the toxic and side effects in the treatment process.Based on various nanomaterials,such as calcium carbonate,DNA tetrahedron,silicon dioxide and metal-organic framework,we have designed and prepared a series of biocompatible and functional nanobiological composites to improve the immunotherapeutic effect of cancer in this paper.It mainly includes the following sections:1.We presented a tumor acidity activatable and Ca²⁺-assisted immuno-nanoagent to synergistically promote T cell activation and enhance cancer immunotherapy.When immuno-nanoagent reached the acidic tumor microenvironment,Ca CO₃ matrix disintegrated to release immune stimulants?Cp G ODNs and IDOi?and Ca²⁺.Cp G ODNs were responsible for triggering dendritic cell maturation to increase the immunogenicity to activate T cells.And IDOi can inhibit the oxidative catabolism of tryptophan to kynurenine for preventing T-cell anergy and apoptosis.Due to the complexity of immunosuppressive microenvironment,it is difficult to restore T cell activation by inhibiting only one pathway.Fortunately,the released Ca²⁺can promote the activation and proliferation of T cells in support of the immune stimulants.In vivo experiments demonstrated that our Ca²⁺-assisted immuno-nanoagent can significantly suppress tumor progression and protect mice from tumor rechallenge due to the long-term memory effect.This immunotherapeutic strategy may provide more possibilities for clinical applications such as treating cancer and preventing relapse.2.We presented a functionalized DNA tetrahedron nanoregulator to specifically trigger ER stress for enhancing cancer immunotherapy.The nanoregulator located into ER organelles by binding to the sulphonamide receptor of cancer cells.Then glucose depletion and reactive oxygen species?ROS?generation caused a strong ER stress response to induce immunogenic cell death?ICD?to expose tumor immunogens.Thereafter,the dendritic cell?DC?maturation was promoted,and T cell proliferation and infiltration were stimulated to advance the cancer immunotherapy.Combined with immune checkpoint inhibitor??-PD-1?,the ER stress triggered nanoregulator exhibited significant suppression for breast cancer and melanoma.3.We presented a dendritic cell-like biomimetic nanoparticle?DMSNs³@HA?to improve immunotherapy by synergistically activating T cells and breaking their immune"brake".DMSNs³@HA was constructed by dendritic mesoporous silica nanoparticle as nanocarrier,anti-CD3 and anti-CD28 for mimicking dendritic cells to activate T cells,anti-PD-1 for blocking the pathway of PD-1/PD-L1,and hyaluronic acid for specifically target to tumor tissue.As injected intravenously,the DMSNs³@HA involving T cell activation reagent and immune checkpoint inhibitor regulated the behavior of T cells and elicited intense antitumor immunity with“1+1>2”effect for inhibiting immunosuppressive tumor.4.We developed a chemo-immunotherapy strategy based on metal-organic framework materials for the treatment of breast cancer.In this system,doxorubicin?DOX?of ZIF?DAC?-DOX was released to cause the ICD of cancer cells,with release of adenosine triphosphate?ATP?.Then,in the acid tumor environment with ATP,ZIF collapsed and its internal imine bond fractured to release decitabine?DAC?.The DAC can reverse the DNA methylation of cancer cells to further promote cancer chemotherapy.In addition,cancer cells that undergo ICD released large amounts of immunogens,which stimulated the immune response to recruit more T cells into the tumor.Meanwhile,the free DAC can also reverse the DNA methylation of T cells and alleviate the depletion and incompetence of T cells.Combined with immunosuppressive agents,the immune response is expected to have good inhibitory effect on distal tumors.