Self‐Activatable Multi‐Module Nanoelectrode Triggering Electro‐Driven Pyroptosis in Cancer Cells Boost Anti‐Tumor Immunity

Abstract Pyroptosis holds significant promise in facilitating tumor immunotherapy, but its efficiency is hindered by the indiscriminate pyroptotic killing of cells within cancer tissues and inadequate expression of gasdermin in cancer cells. Herein, a self‐activatable multi‐module nanoelectrode (HMPD) is presented, precisely evoking gasdermin D (GSDMD)‐dependent pyroptosis in cancer cells via GSH‐activatable electrodynamic therapy (EDT) and Mn 2+ ‐initiated epigenetic reprogramming. HMPD contains core of platinum nanocluster (PtNCs) as electric‐catalytic module and cloaked by electric‐shield module (hyaluronic acid (HA)‐tethered MnO 2 nanoflower, HMNFs), along with the interlayer‐location of epigenetic reprogramming module (Mn 2+ ‐activating DNA Methyltransferase1 (DNMT1) mRNA‐cleavage DNAzymes, DDzymes). Profiting from the cloaking of HMNFs, an inert material for EDT, the electrodynamic and epigenetic reprogramming activities of HMPD are silenced. Due to high‐level glutathione (GSH)‐mediated HMNFs dissociation in cancer cells, the electrodynamic activity is awakened through PtNCs exposure, triggering hydroxyl radical (·OH) generation under a square‐wave alternating current (AC), enabling EDT‐driven GSDMD‐dependent pyroptosis. Meanwhile, epigenetic reprogramming activities are activated under the action of Mn 2+ ions‐initiated DDzymes, which unclocked the GSDMD expression by preventing DNMT1‐dominated promoter hypermethylation, further sensitizing EDT‐driven pyroptosis. The cooperation of electrodynamic therapy and epigenetic reprogramming therapy from nanoelectrode can fully play the therapeutic potency of pyroptosis, providing an alternative approach to expand cancer immunotherapy.