Construction Of Photoresponsive Nanosystems For Cancer Photo-Immunotherapy

Malignant tumors are currently one of the most deadly diseases in the world,posing a serious threat to human health.Traditional methods,like radiotherapy,chemotherapy,and surgery,still have limitations such as large side effects,easy recurrence,and high metastatic rate.Phototherapy,including photodynamic therapy(PDT)and photothermal therapy(PTT),is a new therapeutic modality for tumors and has attracted significant attention owing to a series of advantages,such as high tumor ablation rate,strong spatial controllability,and small side effects on normal tissues.Although this method is effective in several cases,the application of traditional smallmolecule phototherapeutic agents is severely limited by their lack of targeting and poor pharmacokinetics.Moreover,the complex tumor microenvironment makes PDT and PTT models challenging,for example,the hypoxic environment in the tumor reduces the effect of oxygen-dependent PDT,and the tumor has strong heat resistance to PTT.Emerging nanomaterials can target and enrich tumor sites,reduce systemic toxicity,and improve therapeutic efficiency.The therapeutic effects of PDT combined with nanomaterial-based PTT are particularly significant.First,PDT can enhance the sensitivity of tumor cells to PTT by interfering with the tumor’s microenvironment.Second,the heat generated by PTT can increase blood flow,improve oxygen supply,and enhance the therapeutic effect of PDT.However,complete eradication with PTT and PDT is difficult because the tumor can easily metastasize and relapse.Combining phototherapy with immunotherapy,when phototherapy triggers immunogenic cell death(ICD)and further combining it with an immunoadjuvant to stimulate the tumor immunosuppressive microenvironment,can significantly improve the immunotherapy effect.Therefore,this combination therapy can not only eradicate the primary tumor but also inhibit tumor recurrence and metastasis through the immune response.However,the research on multifunctional photoimmunotherapeutic nanomaterials is still in its infancy.There are few reports on nanosystems that combine photodynamic and photothermal therapies,and further integrate Toll-like receptor agonists.Therefore,it is urgent to develop multifunctional,safe,and efficient nanosystems for photosynergistic immunotherapy.In this paper,three novel photoresponsive nanosystems have been constructed for the study of cooperative immunotherapy in tumor phototherapy.Firstly,in order to solve the problems of poor targeting and water solubility of traditional photodynamic agents,carbon quantum dots(CDs)with green fluorescence were prepared by using natural vitamin riboflavin(VB2)as raw material for the photodynamic therapy of tumors.Compared to VB2,the CDs have higher water solubility and biocompatibility.And the efficiency of generating ROS is 3.63 times that of VB2,achieving efficient PDT treatment at the tumor cell level.However,the therapeutic effects of a single PDT session are limited.Next,we designed a red fluorescent carbon point with the dual effects of PDT and PTT based on zinc tetraphenyl porphyrin and further used the CDs as a crosslinking agent and hyaluronic acid(HA-CHO)to construct an injectable hydrogel system(CD@hydrogel)using the Schiff base reaction.The preparation process is simple and avoids complex embellishments.The CD@hydrogel exhibited good photothermal properties under light,with a photothermal conversion efficiency of 37%and excellent singlet oxygen generation ability.Both in-vitro and in-vivo experiments showed that the hydrogel was highly biologically safe and could effectively inhibit tumor growth.To better stimulate the immune response and inhibit the recurrence and metastasis of tumors,we constructed a novel nanoplatform(MPSNs)that integrates PDT/PTT and the immune response based on zinc tetraphenyl porphyrin and silica.The particles had a hexagonal shell structure with zinc tetraphenyl porphyrin as the core and mesoporous silica as the shell,loaded with the toll-like receptor agonist,R837.MPSNs can simultaneously achieve PDT and PTT of tumors under single-laser irradiation and can effectively kill the tumor at the primary site and release DAMPs.Simultaneously,the released R837 improves the tumor immunosuppressive microenvironment,enhances the efficiency of dendritic cells in presenting antigens to lymph nodes,and initially stimulates the immune response of the body.Furthermore,the anti-PD-L1 antibody was used to block the PD-1/PD-L1 immune checkpoint,significantly improving the infiltration of T cells and enhancing the immune response of the body.Therefore,this treatment model can not only eradicate the tumor at the primary site but also eliminate residual tumor cells through the immune response of the body,effectively inhibiting the metastasis and recurrence of the tumor.