Defect‐Regulated Hetero‐Trimetallic Nanocatalysts Augment Sonocatalytic Dynamic Therapy by Charge Transfer Facilitation and Ferroptosis Cascade Induction

Sonocatalytic dynamic therapy (SCDT) is an emerging non-invasive anticancer strategy that employs ultrasound to activate sonocatalysts for the generation of reactive oxygen species (ROS). The therapeutic efficacy of this process is fundamentally governed by the intrinsic performance of the sonocatalyst. However, the artificial engineering of high-performance ROS-generating sonocatalysts faces significant challenges, including low catalytic efficiency, high toxicity, and off-target accumulation. Herein, we construct the distinct two-dimensional ultrathin hetero-trimetallic nanocatalysts rich in oxygen vacancies for efficient SCDT against tumor. This study elucidates the critical role of multi-metal coordination bonds and abundant defects in modulating intrinsic sonocatalytic activity. The derived trimetallic-organic framework nanosheets, featuring uniformly dispersed iron, cobalt, and nickel hetero-single atoms, effectively optimize the active sites, thereby providing robust sonocatalytic activity for efficient ROS generation. Furthermore, the defect-driven sonocatalytic process mitigates the limitations of ligand-to-metal charge transfer, significantly enhancing the charge transfer efficiency. The consequent ROS burst acts as a redox signaling molecule that amplifies oxidative stress within the tumor microenvironment. Concurrently, ROS-mediated intervention in the glutathione peroxidase 4 and long-chain acyl-CoA synthetase 4 pathways promotes the lipid peroxidation, activating the ferroptosis cascade and efficiently inhibiting tumor growth. These findings underscore the considerable prospects of defect-rich sonocatalysts in versatile biomedical applications.