The Construction Of Homologous Targeting Free Radical Nanogenerator And Its Application In Chemo/Chemodynamictherapy And Immunotherapy Synergistic Therapy Of Non-Small Cell Lung Cancer

Non-small-cell Lung Cancer is one of the cancers with the highest fatality rate in the world.Due to the high incidence and mortality rate,Non-small-cell Lung Cancer urgently needs researcher to develop effective treatments.Platinum based chemotherapy drugs such as CISPLATIN are widely used in non-small-cell lung cancer,but their efficacy is limited by inherent or acquired drug resistance,drug side effect and immunosuppressive tumor microenvironment.Immunotherapy is an emerging therapy to improve the treatment of lung cancer,but the autoimmune risks and high cost of immunotherapy agent limit its application in non-small-cell lung cancer.As a result,chemotherapy drugs and immunotherapy for non-small-cell Lung Cancer have not yet achieved satisfactory results.Based on this,metal organic framework（MOF）was synthesized by hydrothermal method,and the iron ions in MOF was complexed with phenolic hydroxyl of tannic acid（TA）to form a radical nanogenerator.Due to the porous structure of MOF,the chemotherapeutic drug cisplatin（CDDP）was loaded through physical adsorption and hydrophobic force,and PD-L1 aptamer（Apt）was loaded through electrostatic adsorption,and then wrapped with tumor cell membrane to form a homologous targeted M@MOF/TA-CDDP-Apt（M@MTCA）nanocoplexes.In the Lewis lung cancer cell line（LL/2）tumor model,M@MTCA is degraded in the acidic tumor microenvironment,and CDDP,Fe³⁺and Apt are released from the nanocomposite,which is expected to specifically deliver the drug to the tumor site playing an anti-tumor effect effect.In addition to its chemotherapeutic effect,CDDP also increases the level of H₂O₂in tumor cells through a series of cascade reaction.At the same time,TA acts as a reducing agent to accelerate the conversion of Fe³⁺to Fe²⁺,so that M@MTCA can quickly catalyze the production of highly cytotoxic·OH.The radical nanogenerator M@MTCA induces tumor immunogenic death through above chemotherapy and chemodynamic therapy,reverses low immunogenicity"cold"tumors into"hot"tumors,and effectively recruits and activates dendritic cells（DCs）,and further activate CD8⁺T cells.In addition,the degradation of the nanocomplex releases a large number of PD-L1 nucleic acid aptamers,alleviating the negative immune regulation of the PD-1/PD-L1 pathway,and enhancing the anti-tumor immune response mediated by CD8⁺T cells.Therefore,a radical nanogenerator with cascade release of hydroxyl radical ability in tumor cells was constructed in this study.Through efficiently loading cisplatin to compensate the consumption of cancer cellular H₂O₂content,radical nanogenerator enhance the chemodynamic efficacy,achieving effective antigen presentation.And through loaded PD-L1 aptamer,radical nanogenerator realizes relief of immunosuppression and effectively activates the tumor immune response to synergistic tumor therapy.The treatment strategy of this study remedy shortcomings of a single treatment plan,achieves a synergistically enhanced anti-tumor effect,and reduces the risk of non-small cell lung cancer recurrence.