Excess intracellular H_(2)S induces destructive mitochondrial toxicity,while overload of Zn^(2+)results in cell pyroptosis and potentiates the tumor immunogenicity for immunotherapy.However,the precise delivery of bot...Excess intracellular H_(2)S induces destructive mitochondrial toxicity,while overload of Zn^(2+)results in cell pyroptosis and potentiates the tumor immunogenicity for immunotherapy.However,the precise delivery of both therapeutics remains a great challenge.Herein,an electrically activable ZnS nanochip for the controlled release of H_(2)S and Zn^(2+)was developed for enhanced gas-ionic-immunotherapy(GIIT).Under an electric field,a locality with particularly high concentrations of H_(2)S and Zn^(2+)was established by the voltage-controlled degradation of the ZnS nanoparticles(NPs).Consequently,the ZnS nanochip-mediated gas-ionic therapy(GIT)resulted in mitochondrial membrane potential depolarization,energy generation inhibition,and oxidative stress imbalance in tumor cells.Interestingly,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes(cGAS-STING)signaling pathway was activated due to the mitochondrial destruction.Moreover,the released Zn^(2+)resulted in the increase of the intracellular Zn levels and cell pyroptosis,which enhanced the immunogenicity via the release of damage-associated molecular patterns(DAMPs).In vitro and in vivo studies revealed that the ZnS nanochip-based GIT effectively eliminated the tumors under an electric field and mobilized the cytotoxic T lymphocytes for immunotherapy.The combination withαCTLA-4 further promoted the adaptive immune response and inhibited tumor metastasis and long-term tumor recurrence.This work presented an electrically activable ZnS nanochip for combined immunotherapy,which might inspire the development of electric stimulation therapy.展开更多
基金supported by the National Research Programs of China(2022YFB3804600)the National Natural Science Foundation of China(52472288,U20A20254,and 52072253)+3 种基金Collaborative Innovation Center of Suzhou Nano Science and Technology,Suzhou Key Laboratory of Nanotechnology and Biomedicine,Jiangsu Natural Science Fund for Distinguished Young Scholars(BK20211544)111 Project,and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices,Science and Technology Development Fund Macao SAR(0118/2023/RIA2,0064/2024/AMJ,and 0016/2024/RIA1)Natural Science Foundation of Shandong Province(ZR2021QH315)Suzhou Key Laboratory of Nanotechnology and Biomedicine,and Key Laboratory of Structural Deformities in Children of Suzhou(Szs2022018).
文摘Excess intracellular H_(2)S induces destructive mitochondrial toxicity,while overload of Zn^(2+)results in cell pyroptosis and potentiates the tumor immunogenicity for immunotherapy.However,the precise delivery of both therapeutics remains a great challenge.Herein,an electrically activable ZnS nanochip for the controlled release of H_(2)S and Zn^(2+)was developed for enhanced gas-ionic-immunotherapy(GIIT).Under an electric field,a locality with particularly high concentrations of H_(2)S and Zn^(2+)was established by the voltage-controlled degradation of the ZnS nanoparticles(NPs).Consequently,the ZnS nanochip-mediated gas-ionic therapy(GIT)resulted in mitochondrial membrane potential depolarization,energy generation inhibition,and oxidative stress imbalance in tumor cells.Interestingly,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes(cGAS-STING)signaling pathway was activated due to the mitochondrial destruction.Moreover,the released Zn^(2+)resulted in the increase of the intracellular Zn levels and cell pyroptosis,which enhanced the immunogenicity via the release of damage-associated molecular patterns(DAMPs).In vitro and in vivo studies revealed that the ZnS nanochip-based GIT effectively eliminated the tumors under an electric field and mobilized the cytotoxic T lymphocytes for immunotherapy.The combination withαCTLA-4 further promoted the adaptive immune response and inhibited tumor metastasis and long-term tumor recurrence.This work presented an electrically activable ZnS nanochip for combined immunotherapy,which might inspire the development of electric stimulation therapy.
