In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance

  • Signal Transduct Target Ther. 2025 Oct 15;10(1):346. doi: 10.1038/s41392-025-02444-z.
Fei-Ya Yang  #  1  2  3 ,  Ni-Yuan Zhang  #  4 ,  Yang Yang  #  4  5 ,  Dong Chen  1  2  3 ,  Li-Yuan Wu  6 ,  Wen-Kuan Wang  1  2  3 ,  Hao-Xi Wang  1  2  3 ,  Zhuan Wen  4  5 ,  Ming-Ze Cai  4 ,  Hao-Ze Li  4  5 ,  Haojie Huang  7 ,  Hong-Wei An  8 ,  Hao Wang  9  10 ,  Nian-Zeng Xing  11  12  13
Affiliations
  • 1. Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3. Beijing Key Laboratory of Urologic Cancer Cell and Gene Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4. CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Zhongguancun, Beijing, China.
  • 5. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, China.
  • 6. Departments of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 7. Department of Urology, The First Affiliated Hospital, Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 8. CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Zhongguancun, Beijing, China. [email protected].
  • 9. CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Zhongguancun, Beijing, China. [email protected].
  • 10. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 11. Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 12. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 13. Beijing Key Laboratory of Urologic Cancer Cell and Gene Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41087345 DOI: 10.1038/s41392-025-02444-z
Abstract

Castration-resistant prostate Cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate Cancer to PSMA- and AR-positive castration-resistant prostate Cancer, except for neuroendocrine prostate Cancer, which provides a new therapeutic strategy for the treatment of prostate Cancer.

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