Electric Pulse Regulated MXene Based Nanozymes for Integrative Bioelectricity Immuno-Cancer Therapy

Non-thermal bioelectricity cancer therapy (BECT), utilizing high-voltage and high-frequency pulsed electric fields, represents a novel approach in oncological treatment. Herein, an electric pulse-regulated MXene-based nanozyme (MXenzyme)-catalyzed bioelectricity cancer cell eradication is presented while activating immunogenic responses for integrative BECT immunotherapy. Ti₃C₂ MXenzyme, the most conductive member of the MXene family, is synthesized and characterized for superior electrical properties in an aqueous environment. Incorporating MXenzyme into BECT significantly enhances irreversible cancer cell death and expands the ablation area compared to BECT alone. Computational modeling reveals that MXenzyme on cell membranes generates localized hotspots of current density and electric field (E-field) concentration during BECT application. MXenzyme catalytic effect in BECT induced three primary cytotoxic mechanisms: 1) direct membrane depolarization and irreversible poration, 2) disruption of voltage-gated ion channels, and 3) generation of cytotoxic reactive oxygen species. These combined mechanisms contributed to immunogenic cell death. Immunological profiling of the tumor microenvironment modulated by MXenzyme-BECT confirmed its profound cytotoxic impact and activation of a potent anti-tumor immune response. Translational potential of MXenzyme-BECT is evaluated using computational modeling-based pre-treatment planning and in combination with immune checkpoint inhibitor therapy. Findings underscore MXenzyme's pivotal role as a highly electric-regulated enzymatic catalyst, significantly enhancing BECT efficacy and advancing integrative BECT-immunotherapy strategies.