An electrically activable nanochip to intensify gas-ionic-immunotherapy

Abstract

Excess intracellular H₂S induces destructive mitochondrial toxicity, while overload of Zn²⁺ 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 H₂S and Zn²⁺ was developed for enhanced gas-ionic-immunotherapy (GIIT). Under an electric field, a locality with particularly high concentrations of H₂S and Zn²⁺ 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 Zn²⁺ 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 with αCTLA-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.