Yiming Liu , Guangzhe Li , Guibin Wang , Yang Wang , Jianlong Su , Zhihao Wu , Ruimin Wang , Xiaomai Zhang , Jinrong Li , Guanyi Zhang , Yuxuan Zhang , Xu Wang , Yuanhang Yao , Mingrui Bai , Ruoshi Wang , Lei Wang , Jingdong Zhang , Kun Shao
{"title":"超声激活纳米疫苗可扩增双模态活性氧用于癌症超声免疫治疗","authors":"Yiming Liu , Guangzhe Li , Guibin Wang , Yang Wang , Jianlong Su , Zhihao Wu , Ruimin Wang , Xiaomai Zhang , Jinrong Li , Guanyi Zhang , Yuxuan Zhang , Xu Wang , Yuanhang Yao , Mingrui Bai , Ruoshi Wang , Lei Wang , Jingdong Zhang , Kun Shao","doi":"10.1016/j.jconrel.2025.114285","DOIUrl":null,"url":null,"abstract":"<div><div>Insufficient reactive oxygen species (ROS), including limited ROS bioactivity and poor accumulation efficiency inside tumor cells, remain a major barrier to the effectiveness of sonodynamic therapy (SDT). Among ROS types, hydroxyl radical (·OH) displays superior killing efficiency compared to singlet oxygen (<sup>1</sup>O₂), while diminishing oxygen reliance. Nevertheless, most existing small molecule sonosensitizers exhibit <sup>1</sup>O<sub>2</sub>-predominance under ultrasound (US). In this study, we discovered that RB-Biotin, a derivative of the classical <sup>1</sup>O<sub>2</sub> sonosensitizer Rose Bengal (RB), remarkably augmented ·OH production without compromising <sup>1</sup>O<sub>2</sub> yield under US irradiation. The dual-modal ROS generation mechanism was elucidated by computational studies of density functional theory (DFT). RB-Biotin was further loaded onto MnO<sub>2</sub>-based nanocarriers to obtain the ultrasound-enabled nanovaccines, BMRP. The MnO<sub>2</sub> scaffold not only transformed the endogenous hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) into oxygen to fuel <sup>1</sup>O<sub>2</sub> production by RB-Biotin, but also inhibited ROS depletion by blocking intracellular glutathione (GSH), creating a dual-modal ROS “reservoir” within tumor cells. In a mouse hepatocellular carcinoma (HCC) model, BMRP demonstrated a potent sono-immune therapeutic effect through synergistic dual-modal ROS (<sup>1</sup>O<sub>2</sub> and ·OH) amplification and locally released Mn<sup>2+</sup>-favored immune activation, leading to remarkable tumor regression and robust anti-tumor immune responses. This work represents a paradigm shift in SDT by transitioning from mono-modal to dual-modal ROS generation, leveraging the complementary oxidative mechanisms of <sup>1</sup>O<sub>2</sub> and ·OH to improve SDT efficacy. By integrating the strengths of RB-Biotin and MnO<sub>2</sub> nanocarriers, this approach not only overcomes intrinsic limitations of conventional SDT, but also expands the application of ultrasound-driven cancer therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"388 ","pages":"Article 114285"},"PeriodicalIF":11.5000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ultrasound-activatable nanovaccines amplify dual-modal ROS for cancer sono-immunotherapy\",\"authors\":\"Yiming Liu , Guangzhe Li , Guibin Wang , Yang Wang , Jianlong Su , Zhihao Wu , Ruimin Wang , Xiaomai Zhang , Jinrong Li , Guanyi Zhang , Yuxuan Zhang , Xu Wang , Yuanhang Yao , Mingrui Bai , Ruoshi Wang , Lei Wang , Jingdong Zhang , Kun Shao\",\"doi\":\"10.1016/j.jconrel.2025.114285\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Insufficient reactive oxygen species (ROS), including limited ROS bioactivity and poor accumulation efficiency inside tumor cells, remain a major barrier to the effectiveness of sonodynamic therapy (SDT). Among ROS types, hydroxyl radical (·OH) displays superior killing efficiency compared to singlet oxygen (<sup>1</sup>O₂), while diminishing oxygen reliance. Nevertheless, most existing small molecule sonosensitizers exhibit <sup>1</sup>O<sub>2</sub>-predominance under ultrasound (US). In this study, we discovered that RB-Biotin, a derivative of the classical <sup>1</sup>O<sub>2</sub> sonosensitizer Rose Bengal (RB), remarkably augmented ·OH production without compromising <sup>1</sup>O<sub>2</sub> yield under US irradiation. The dual-modal ROS generation mechanism was elucidated by computational studies of density functional theory (DFT). RB-Biotin was further loaded onto MnO<sub>2</sub>-based nanocarriers to obtain the ultrasound-enabled nanovaccines, BMRP. The MnO<sub>2</sub> scaffold not only transformed the endogenous hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) into oxygen to fuel <sup>1</sup>O<sub>2</sub> production by RB-Biotin, but also inhibited ROS depletion by blocking intracellular glutathione (GSH), creating a dual-modal ROS “reservoir” within tumor cells. In a mouse hepatocellular carcinoma (HCC) model, BMRP demonstrated a potent sono-immune therapeutic effect through synergistic dual-modal ROS (<sup>1</sup>O<sub>2</sub> and ·OH) amplification and locally released Mn<sup>2+</sup>-favored immune activation, leading to remarkable tumor regression and robust anti-tumor immune responses. This work represents a paradigm shift in SDT by transitioning from mono-modal to dual-modal ROS generation, leveraging the complementary oxidative mechanisms of <sup>1</sup>O<sub>2</sub> and ·OH to improve SDT efficacy. By integrating the strengths of RB-Biotin and MnO<sub>2</sub> nanocarriers, this approach not only overcomes intrinsic limitations of conventional SDT, but also expands the application of ultrasound-driven cancer therapy.</div></div>\",\"PeriodicalId\":15450,\"journal\":{\"name\":\"Journal of Controlled Release\",\"volume\":\"388 \",\"pages\":\"Article 114285\"},\"PeriodicalIF\":11.5000,\"publicationDate\":\"2025-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Controlled Release\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0168365925008983\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Controlled Release","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168365925008983","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Ultrasound-activatable nanovaccines amplify dual-modal ROS for cancer sono-immunotherapy
Insufficient reactive oxygen species (ROS), including limited ROS bioactivity and poor accumulation efficiency inside tumor cells, remain a major barrier to the effectiveness of sonodynamic therapy (SDT). Among ROS types, hydroxyl radical (·OH) displays superior killing efficiency compared to singlet oxygen (1O₂), while diminishing oxygen reliance. Nevertheless, most existing small molecule sonosensitizers exhibit 1O2-predominance under ultrasound (US). In this study, we discovered that RB-Biotin, a derivative of the classical 1O2 sonosensitizer Rose Bengal (RB), remarkably augmented ·OH production without compromising 1O2 yield under US irradiation. The dual-modal ROS generation mechanism was elucidated by computational studies of density functional theory (DFT). RB-Biotin was further loaded onto MnO2-based nanocarriers to obtain the ultrasound-enabled nanovaccines, BMRP. The MnO2 scaffold not only transformed the endogenous hydrogen peroxide (H2O2) into oxygen to fuel 1O2 production by RB-Biotin, but also inhibited ROS depletion by blocking intracellular glutathione (GSH), creating a dual-modal ROS “reservoir” within tumor cells. In a mouse hepatocellular carcinoma (HCC) model, BMRP demonstrated a potent sono-immune therapeutic effect through synergistic dual-modal ROS (1O2 and ·OH) amplification and locally released Mn2+-favored immune activation, leading to remarkable tumor regression and robust anti-tumor immune responses. This work represents a paradigm shift in SDT by transitioning from mono-modal to dual-modal ROS generation, leveraging the complementary oxidative mechanisms of 1O2 and ·OH to improve SDT efficacy. By integrating the strengths of RB-Biotin and MnO2 nanocarriers, this approach not only overcomes intrinsic limitations of conventional SDT, but also expands the application of ultrasound-driven cancer therapy.
期刊介绍:
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