Metal‐Peptide Frameworks Reconfigure Biopiezoelectricity for Coupled Sonocatalysis and PROTAC Degradation in Tumor Therapy

ABSTRACT Sonodynamic therapy (SDT) relies on sonosensitizers to convert ultrasonic mechanical energy into reactive oxygen species (ROS), yet efficient and biocompatible acoustically responsive materials remain limited. Here, we propose a metal coordination strategy to regulate biopiezoelectric materials. Cu 2+ reconstructs the assembly and charge distribution of diphenylalanine (FF), constructing metal‐peptide framework nanospheres (CuFF) with an effective local piezoresponse of approximately 168 pm V −1 . Density functional theory calculations reveal that asymmetric local coordination generates directional dipoles and anisotropic charge distribution, while ionic displacement within the flexible framework dominates the piezoelectric response. Under ultrasound, piezoelectric polarization, and enhanced cavitation synergistically promote the generation of •OH, •O 2− , and 1 O 2 . Surface modification and loading of a BET‐targeting PROTAC produce CuFF@PROTAC@PEG (CPP). Combined with ultrasound, CPP induces ROS generation, mitochondrial damage, and transcriptomic stress responses, while enhancing BRD3/BRD4 degradation and c‐Myc suppression, achieving a 91.3% killing rate in HeLa cells and a 92.6% tumor inhibition rate in tumor‐bearing mice. This work demonstrates that metal‐coordination‐mediated reconstruction of peptide assembly and interfacial charge distribution can enhance and harness biopiezoelectricity for ultrasound‐responsive catalysis, as validated in the CuFF system.