Disrupt Mitochondrial Proton Gradients via Flexoelectric Catalysis to Deplete Tumor Energy and Enhance Immunotherapy

Abstract Mitochondria, recognized as the cellular powerhouse, provide a continuous stream of energy essential for the rapid proliferation and elevated metabolic demands of tumor cells. Herein, a flexoelectric nanocatalyst, SrTiO₃/RGD/TPP (SRT), is engineered to disrupt mitochondrial proton gradients and ionic balance through ultrasound‐induced flexoelectric catalysis. This interference impedes mitochondrial energy production, resulting in tumor cell apoptosis due to an inadequate energy supply. Upon ultrasound stimulation, the SRT experiences polarization due to the stress gradient, resulting in the separation of positive and negative charges, thereby generating a local electric field. The negative charges interact with protons (H⁺) in the mitochondrial intermembrane space to produce hydrogen (H₂), thereby reducing proton concentration and disrupting the mitochondrial proton gradient, subsequently inhibiting ATP synthesis. Concurrently, the local electric field modifies the mitochondrial membrane potential (MMP), opening the mitochondrial calcium uniporter (MCU) channels and facilitating the influx of calcium ions, resulting in calcium overload and mitochondrial dysfunction, ultimately severing the energy supply to tumor cells. This disruption of energy, when combined with immunotherapy, demonstrates significant tumor inhibition in both in vitro and in vivo models. Through the integration of flexoelectric catalysis and immunotherapy, this study demonstrates potent anti‐tumor effects and proposes new research directions in nanomedicine.