An Electronegativity‐Modulated Piezoelectric Metal–Organic Framework for Tumor Piezocatalytic Ferroptosis

Abstract Piezoelectric materials have emerged as versatile tools for ultrasound‐triggered cancer therapy, yet their clinical application is constrained by inefficient charge separation and the limited availability of catalytic substrates in the tumor microenvironment. Here, an electronegativity‐modulated piezoelectric metal–organic framework (CapMOF@HA) is reported through controlled heteroepitaxial growth of CaO 2 on pMOFs, followed by surface functionalization with hyaluronic acid (HA) for tumor‐targeting capability for enhanced piezocatalytic therapy. Of note, the electronegativity‐modulated heterogeneous interfaces between CaO 2 and pMOF promote the separation of electron–hole pairs while suppressing recombination through the electronegativity effect, significantly amplifying piezocatalytic reactive oxygen species (ROS) generation (•OH, 1 O 2 , and •O 2 ⁻) under ultrasound stimulation. Furthermore, the controlled decomposition of calcium peroxide provides a continuous supply of H 2 O 2 and O 2 as catalytic substrates, while releasing Ca 2+ to induce calcium overload, triggering mitochondrial dysfunction and glutathione peroxidase 4 inhibition for ferroptosis induction. This strategy integrates enhanced piezoelectric catalysis with ferroptosis induction, overcoming long‐standing limitations in piezocatalytic systems to achieve precise and robust tumor ablation. By combining substrate self‐sufficiency with multifunctional therapeutic mechanisms, this work establishes tumor piezocatalytic ferroptosis as a transformative platform for next‐generation piezoelectric cancer therapy.