Mitochondrion-specific organometallic sonosensitizer boosts synergistic sonodynamic therapy for augmented ferroptosis to trigger systemic immunity

Drug design and mechanisms are essential for advancing our understanding of sonosensitizer development, the biological processes underlying anti-tumor responses, and guiding optimal treatment strategies. This article highlighted a remarkably efficient organometallic compound (IRCur-Pt), which has shown remarkable efficiency in reducing toxicity and increasing sono-sensitivity. Our research offers a theoretical framework to explain the superior performance of IRCur-Pt, highlighting its precise targeting of mitochondria and its ability to generate a substantial amount of 1O2 upon ultrasound stimulation, directly killing cancer cells. Notably, IRCur-Pt disrupted mitochondrial structure, resulting reduced ATP capacity, interference with NADPH, depletion of GSH, inhibition of GPX4 activity, accumulation of lipid peroxidation, and subsequent occurrence of ferroptosis. Furthermore, proteomic analysis strongly supported IRCur-Pt’s anti-tumor mechanisms in vivo, confirming the activation of reactive oxygen species (ROS) ferroptosis signaling pathways, along with T cell receptor signaling pathways. Consistent anti-tumor effects were observed in animal models. In systemic immune assessments, IRCur-Pt+US effectively activated adaptive T cells while suppressing the proliferation of Treg cells, highlighting its substantial therapeutic potential. Through a multifaceted approach, IRCur-Pt demonstrated outstanding anti-tumor performance under US irradiation. This study comprehensively introduced novel perspectives for drug design, inducing cancer cell apoptosis, amplifying ferroptosis, triggering systemic immunity, and providing an innovative avenue for cancer treatment. [Display omitted] •The advantageous confirmation of sono-sensitivity performance through comprehensive research involving theoretical and experimental results.•Efficient ROS further caused ICD in cancer cells, promoting the secretion of key cytokines such as TNF-α, and IFN-γ, as well as activation of DCs, leading to immune response.•Under US stimulation, IRCur-Pt induced ferroptosis, which is a unique mechanism that can effectively avoid challenges faced by various conventional drugs, such as tumor escape.•In-depth exploration and mechanism validation of proteomics have elucidated the biological characteristics of this organometallic sonosensitizer molecule, contributing to a comprehensive chain-based research approach.