Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy

Meng-Die Yang; Kang Fang; Xiao-Yi Zhang; Gang Yang; He-Qing Yi; Le Cai; Shan-Shan Qin; Xin-Da Yang; Rong Rong; Shuo Shi; Fei Yu

doi:10.1186/s40779-025-00673-5

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Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy

RESEARCH | Updated：2026-01-29

- Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy
- Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy
- “在癌症靶向α治疗领域，开发了一种双重锁定的预靶向策略，将负载铂IV（PtIV）的水凝胶纳米颗粒（HNPs）和负载镭223（223Ra）的HNPs整合到反向电子需求Diels-Alder（IEDDA）激活的药物递送系统中。这种笼式双锁定方法能够在肿瘤部位实现精确的预靶向积聚，然后在IEDDA触发激活后快速解离和控制223Ra和PtIV的释放，从而确保高肿瘤特异性，同时最大限度地减少全身暴露。TAT和化疗的协同组合有效地破坏了氧化还原稳态，诱导了免疫原性细胞死亡（ICD），并引发了强烈的抗肿瘤免疫反应。此外，当与程序性死亡配体1（PD-L1）阻断结合使用时，该策略显著增强了全身抗肿瘤免疫，从而有力地抑制了肿瘤的生长和转移。这些发现强调了双锁定预靶向策略的潜力，通过提高治疗效果和解决放射性核素泄漏的关键挑战来推进TAT，为下一代精确靶向放射性药物铺平了道路。”
- Military Medical Research 2025年12卷
- Affiliations：
  
  1.Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, School of Chemical Science and Engineering, Shanghai 200072, China
  2.Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai 200072, China
  3.College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
  4.Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou 310022, China
- Author bio：
  
  * Shuo Shi shishuo@tongji.edu.cn
  Fei Yu 0910110013yufei@tongji.edu.cn; yufei_021@163.com
- Funds：
  
  the National Natural Science Foundation of China(82272030;82472028;22277090);the Construction Project of Shanghai Key Laboratory of Molecular Imaging(18DZ2260400);the Natural Science Foundation of Shanghai(23ZR1466700);the Natural Science Foundation of Shandong Province(ZR2025QC1386)
- DOI：10.1186/s40779-025-00673-5
  中图分类号：
- 收稿：2025-05-14，
  
  录用：2025-11-13，
  
  网络首发：2025-12-01，
  
  纸质出版：2025
- Accepted：
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Meng-Die Yang, Kang Fang, Xiao-Yi Zhang, 等. Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy[J/OL]. Military Medical Research, 2025,12.

Meng-Die Yang, Kang Fang, Xiao-Yi Zhang, et al. Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy[J/OL]. Military Medical Research, 2025, 12.
Meng-Die Yang, Kang Fang, Xiao-Yi Zhang, 等. Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy[J/OL]. Military Medical Research, 2025,12. DOI： 10.1186/s40779-025-00673-5.

Meng-Die Yang, Kang Fang, Xiao-Yi Zhang, et al. Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy[J/OL]. Military Medical Research, 2025, 12. DOI： 10.1186/s40779-025-00673-5.

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Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy

Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels–Alder reaction-based self-immolative molecular cage strategy

DOI：10.1186/s40779-025-00673-5