Modulating the Electronic Structure of MnNiS Nanoelectrodes to Activate Pyroptosis for Electrocatalytic Hydrogen-Immunotherapy.

Hydrogen (H) therapy has demonstrated antitumor effect, but the therapeutic efficacy is restricted by the low solubility and nontarget delivery of H. Electrolysis of HO by electrocatalysts sustainably releases enormous amounts of H and inspires the precise delivery of H for tumor therapy. Herein, manganese-doped NiS nanoelectrodes (MnNiS NEs) are designed for the electrocatalytic delivery of H and the activation of antitumor immunity to effectively potentiate H-immunotherapy. Ni atoms featuring empty 3d orbitals reduce the initial energy barrier of the hydrogen evolution reaction (HER) by promoting the adsorption of HO. Moreover, Mn atoms with different electronegativity modulate the electronic structure of Ni atoms and facilitate the desorption of the generated H, thus enhancing the HER activity of the MnNiS NEs. Based on the high HER activity, controllable delivery of H for electrocatalytic hydrogen therapy (EHT) is achieved in a voltage-dependent manner. Mechanistically, MnNiS NE-mediated EHT induces mitochondrial dysfunction and oxidative stress, which subsequently activates pyroptosis through the typical ROS/caspase-1/GSDMD signaling pathway. Furthermore, MnNiS NE-mediated EHT enhances the infiltration of CD8 T lymphocytes into tumors and reverses the immunosuppressive microenvironment. This work demonstrates an electrocatalyst with high HER activity for synergistic gas-immunotherapy, which may spark electrocatalyst-based tumor therapy strategies.