Citation: Kai Li, Hui Fang, Feixia Ruan, Xiaochun Xie, Huicong Zhou, Zhenjun Luo, Dan Shao, Mingqiang Li, Qing Yuan, Fangman Chen, Yu Tao. ROS-neutralizing surface engineering protects immunotoxicity of organic nanoscintillator-directed radiodynamic therapy[J]. Chinese Chemical Letters, ;2025, 36(12): 111261. doi: 10.1016/j.cclet.2025.111261 shu

ROS-neutralizing surface engineering protects immunotoxicity of organic nanoscintillator-directed radiodynamic therapy

Kai Li ^{a, 1} ,
Hui Fang ^{b, 1} ,
Feixia Ruan ^b ,
Xiaochun Xie ^b ,
Huicong Zhou ^a ,
Zhenjun Luo ^c ,
Dan Shao ^b ,
Mingqiang Li ^a ,
Qing Yuan ^{c, *,} ,
Fangman Chen ^{a, *,} ,
Yu Tao ^{a, *,}

a.
Laboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
b.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China
c.
Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing 100039, China

yuanqing@301hospital.com.cn

chenfangman@hotmail.com

taoy28@mail.sysu.edu.cn

Received Date: 17 February 2025
Revised Date: 23 April 2025
Accepted Date: 26 April 2025
Available Online: 27 April 2025

Figures(5)

Despite the promising potential of organic nanoscintillator-mediated radiodynamic therapy (RDT) in enhancing the effectiveness of immunotherapy, their cutaneous phototoxicity exacerbates the risk for immune-related adverse events (irAEs). Herein, we demonstrate that organic nanoscintillators, when combined with checkpoint blockade immunotherapy and exposed to X-ray-induced RDT, can trigger cutaneous irAEs. To address this challenge, we engineered diselenide-bridged silicon coatings on organic nanoscintillators, fine-tuning the steric hindrance of the protective layer by varying its thickness. This strategy enables radiation-triggered reactive oxygen species (ROS) generation while mitigating off-target phototoxicity through neutralizing ROS. By optimizing the steric hindrance to precisely control energy transfer between the organic nanoscintillators and surrounding oxygen molecules, we effectively reduce phototoxicity and mitigate off-tumor effects through engineered surface protection. Under X-ray irradiation exposure, the steric hindrance is rapidly deactivated through the dissociation of the silicon coating, activating RDT and inducing abundant ROS generation within tumor cells. In an orthotopic 4T1 breast cancer model, intravenous administration of these surface-engineered nanoscintillators, combined with anti-programmed death-1 (anti-PD-1) antibodies, results in robust anti-tumor immune responses, while minimizing cutaneous irAEs. This work offers valuable insights into how surface engineering can modulate the delicate balance between anti-tumor efficacy and off-tumor toxicity in nanoscintillator-mediated RDT.
- Organic nanoscintillator,
- Surface modification,
- Radiodynamic therapy,
- ROS,
- Immune-related adverse events
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