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<p>The clinical translation of sonosensitizers is significantly constrained by their suboptimal reactive oxygen species generation (ROS), reduced efficacy under hypoxic conditions, and inadequate accumulation and retention in tumor tissues. To overcome these limitations, we developed a deuterated Ru(II) sonosensitizer (<b>Ru1</b>) that, upon ultrasound irradiation, demonstrated substantially enhanced production of both Type I and Type II ROS compared to its non-deuterated analog <b>TLD1433</b>—a Ru-based photosensitizer currently under clinical investigation. Deuteration not only improved ROS yields but also promoted the oxidative depletion of glutathione, thereby disrupting intracellular redox homeostasis. <i>In vitro</i>, <b>Ru1</b>-mediated sonodynamic therapy (SDT) induced PANoptosis and ferroptosis, culminating in immunogenic cell death. <i>In vivo</i>, the actively targeted nanoplatform <b>Ru1@PEG-RGD</b> nanoparticles exhibited superior tumor-specific accumulation and retention, leading to significantly improved SDT outcomes and robust activation of antitumor immunity. Our work firstly highlights deuteration as a highly effective strategy for augmenting sonosensitizer performance, offering a promising platform for advancing sonodynamic immunotherapy with strong translational potential.</p>

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Deuteration enhances ruthenium sonosensitizers to potentiate antitumor immunity

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Long-Bo Yu,
  • Peng Wang,
  • Qing-Hua Shen,
  • Shuo-Ting Huang,
  • Qi-Xin Guan,
  • Zhi-Yuan Li,
  • Ying-Ying Han,
  • Xin-Yi Zhang,
  • Qing-Yuan Hu,
  • Cai-Ping Tan

摘要

The clinical translation of sonosensitizers is significantly constrained by their suboptimal reactive oxygen species generation (ROS), reduced efficacy under hypoxic conditions, and inadequate accumulation and retention in tumor tissues. To overcome these limitations, we developed a deuterated Ru(II) sonosensitizer (Ru1) that, upon ultrasound irradiation, demonstrated substantially enhanced production of both Type I and Type II ROS compared to its non-deuterated analog TLD1433—a Ru-based photosensitizer currently under clinical investigation. Deuteration not only improved ROS yields but also promoted the oxidative depletion of glutathione, thereby disrupting intracellular redox homeostasis. In vitro, Ru1-mediated sonodynamic therapy (SDT) induced PANoptosis and ferroptosis, culminating in immunogenic cell death. In vivo, the actively targeted nanoplatform Ru1@PEG-RGD nanoparticles exhibited superior tumor-specific accumulation and retention, leading to significantly improved SDT outcomes and robust activation of antitumor immunity. Our work firstly highlights deuteration as a highly effective strategy for augmenting sonosensitizer performance, offering a promising platform for advancing sonodynamic immunotherapy with strong translational potential.