Ultrasound‐Triggered Nanoparticles Induce Cuproptosis for Enhancing Immunogenic Sonodynamic Therapy

Cuproptosis, as a novel mechanism of cell death, holds significant promise for tumor therapy. However, existing studies typically employ methods to induce cuproptosis through endogenous or exogenous pathways, which often fail to achieve precise control in both space and time. Herein, polymeric nanoparticles (RC NPs) are developed that enable precise activation of cuproptosis through acoustic control for tumor-specific treatment. The nanoparticles are fabricated via self-assembly of a degradable, acoustic-sensitive polymer (Poly RA) and a metal-ion-loadable polyphenol-structured polymer (Poly MPN). Ultrasound stimulation cleaved the RC NPs, generating reactive oxygen species (ROS) and promoting the release of copper ions from Poly MPN, leading to the aggregation of lipoylated proteins and depletion of iron-sulfur cluster proteins to introduce cuproptosis. Subsequently, the RC NPs successfully activated the immune system of mice, promoting the maturation of antigen-presenting cells and the activation of T lymphocytes. The nanoparticles exhibited good biosafety and significant tumor inhibition in both orthotopic and patient-derived xenograft (PDX) models. These novel nanoparticles provide a promising modality for the treatment of highly aggressive cancers and a valuable avenue for future clinical applications.