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

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

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. anhw@nanoctr.cn.
  • 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. wanghao@nanoctr.cn.
  • 10 Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China. wanghao@nanoctr.cn.
  • 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. xingnianzeng@126.com.
  • 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. xingnianzeng@126.com.
  • 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. xingnianzeng@126.com.
  • # 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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