Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly l...Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.展开更多
mRNA therapeutics is revolutionizing the treatment concepts toward many diseases including cancer.The potential of mRNA is,however,frequently limited by modest control over site of transfection.Here,we have explored a...mRNA therapeutics is revolutionizing the treatment concepts toward many diseases including cancer.The potential of mRNA is,however,frequently limited by modest control over site of transfection.Here,we have explored a library of multivalent ionizable lipid-polypeptides(MILP)to achieve robust mRNA complexation and tumor-confined transfection.Leveraging the multivalent electrostatic,hydrophobic,and H-bond interactions,MILP efficiently packs both mRNA and plasmid DNA into sub-80 nm nanoparticles that are stable against lyophilization and long-term storage.The best MILP@mRNA complexes afford 8-fold more cellular uptake than SM-102 lipid nanoparticle formulation(SM-102 LNP),efficient endosomal disruption,and high transfection in different cells.Interestingly,MILP@mLuc displays exclusive tumor residence and distribution via multivalencydirected strong affinity and transcytosis,and affords specific protein expression in tumor cells and macrophages at tumor sites following intratumoral injection,in sharp contrast to the indiscriminate distribution and transfection in main organs of SM-102 LNP.Notably,MILP@mIL-12 with specific and efficient cytokine expression generates significant remodeling of tumor immunoenvironments and remarkable antitumor response in subcutaneous Lewis lung carcinoma and 4T1 tumor xenografts.MILP provides a unique strategy to site-specific transfection that may greatly broaden the applications of mRNA.展开更多
基金supported by the National Natural Science Foundation of China(Nos.T2293753,52203194)the National Key R&D Program of China(No.2021YFA1201200)+1 种基金the Natural Science Foundation of Zhejiang Province(No.LR18E030002)2023 Hangzhou West Lake Pearl Project Leading Innovative Youth Team Project.
文摘Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.
基金support from the National Key R&D Program of China(2021YFB3800900,2022YFB3804600)the National Natural Science Foundation of China(NSFC 52373299)is acknowledged.
文摘mRNA therapeutics is revolutionizing the treatment concepts toward many diseases including cancer.The potential of mRNA is,however,frequently limited by modest control over site of transfection.Here,we have explored a library of multivalent ionizable lipid-polypeptides(MILP)to achieve robust mRNA complexation and tumor-confined transfection.Leveraging the multivalent electrostatic,hydrophobic,and H-bond interactions,MILP efficiently packs both mRNA and plasmid DNA into sub-80 nm nanoparticles that are stable against lyophilization and long-term storage.The best MILP@mRNA complexes afford 8-fold more cellular uptake than SM-102 lipid nanoparticle formulation(SM-102 LNP),efficient endosomal disruption,and high transfection in different cells.Interestingly,MILP@mLuc displays exclusive tumor residence and distribution via multivalencydirected strong affinity and transcytosis,and affords specific protein expression in tumor cells and macrophages at tumor sites following intratumoral injection,in sharp contrast to the indiscriminate distribution and transfection in main organs of SM-102 LNP.Notably,MILP@mIL-12 with specific and efficient cytokine expression generates significant remodeling of tumor immunoenvironments and remarkable antitumor response in subcutaneous Lewis lung carcinoma and 4T1 tumor xenografts.MILP provides a unique strategy to site-specific transfection that may greatly broaden the applications of mRNA.
