Tumor Microenvironment Activated Cu Crosslinked Near-Infrared Sonosensitizers for Visualized Cuproptosis-Enhanced Sonodynamic Cancer Immunotherapy.

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth. However, the inevitable accumulation of sonosensitizers in normal tissues not only make it difficult to realize the in situ SDT, but also induces sonodynamic effects in normal tissues. Herein, this work reports the passivation and selective activation strategies for the sonodynamic and near-infrared (NIR) imaging performances of an intelligent antitumor theranostic platform termed Cu-IR783 nanoparticles (NPs). Owing to the ruptured coordination bond between IR783 with Cu ions by responding to tumor microenvironment (TME), the selective activation of IR783 only occurred in tumor tissues to achieve the visualized in-situ SDT. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu⁺-mediated Fenton-like reaction, but also triggered cuproptosis through Cu⁺-induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a distinct paradigm of the integration of SDT, CDT, and cuproptosis in a controlled manner to achieve visualized in-situ antitumor therapy.