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Peer-reviewedCC BY-NC-NDActa pharmaceutica Sinica. B

A peptide-based nano-PROTAC synergistically driving ferroptosis-immunotherapy in triple-negative breast cancer

  • Jiasha Wu1
  • Rui Ji1
  • Luyi Wang1
  • Yurui Zhu1
  • Shiqin Jian1
  • Yan Zuo1
  • Siyao Liu1
  • Yejiao Shi2
  • Xiaochun Hu1
  • Honggang Hu1
  1. 1Department of Chemistry, College of Sciences, School of Medicine, Shanghai University, Shanghai 200444, China
  2. 2Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
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Abstract

Ferroptosis, an emerging mechanism of cell death, provides new targets for the treatment of triple-negative breast cancer (TNBC). Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, is a promising therapeutic target for TNBC. Given that GPX4 is often considered “undruggable”, proteolysis targeting chimeras (PROTACs) offer a powerful means for its degradation. However, conventional PROTACs often face challenges in achieving precise localization and potent activation in vivo. Herein, we engineered a peptide-based nano-PROTAC, named CMVG, which couples VHL- and GPX4-binding peptides with iron-based metal–organic frameworks via a “click” reaction and loads the photosensitizer chlorin e6 (Ce6). CMVG enhances ferroptosis through a dual mechanism: it degrades GPX4 via its PROTAC function to initiate ferroptosis, while generating reactive oxygen species under laser irradiation to mediate photodynamic therapy, thereby intensifying oxidative stress and accelerating ferroptosis. Furthermore, the ferroptosis induced by CMVG is highly immunogenic, triggering immunogenic cell death and reshaping the tumor immune microenvironment, ultimately boosting the anti-TNBC immune response. Additionally, CMVG exhibits excellent targeting and biocompatibility, enabling MRI-guided tumor treatment. This work presents the first peptide-based nano-PROTAC for GPX4 degradation, overcoming major limitations of conventional PROTACs, and offers a promising integrated strategy for treating TNBC.

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Cite

BibTeXRIS
BibTeX
@article{wu2026peptidebased,
  title = {{A peptide-based nano-PROTAC synergistically driving ferroptosis-immunotherapy in triple-negative breast cancer}},
  author = {Jiasha Wu and Rui Ji and Luyi Wang and Yurui Zhu and Shiqin Jian and Yan Zuo and Siyao Liu and Yejiao Shi and Xiaochun Hu and Honggang Hu},
  journal = {Acta pharmaceutica Sinica. B},
  year = {2026},
  month = jul,
  doi = {10.1016/j.apsb.2026.07.045},
  url = {https://europepmc.org/article/PMC/PMC13730232},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A peptide-based nano-PROTAC synergistically driving ferroptosis-immunotherapy in triple-negative breast cancer
AU  - Jiasha Wu
AU  - Rui Ji
AU  - Luyi Wang
AU  - Yurui Zhu
AU  - Shiqin Jian
AU  - Yan Zuo
AU  - Siyao Liu
AU  - Yejiao Shi
AU  - Xiaochun Hu
AU  - Honggang Hu
PY  - 2026
DA  - 2026/07/31
JO  - Acta pharmaceutica Sinica. B
DO  - 10.1016/j.apsb.2026.07.045
UR  - https://europepmc.org/article/PMC/PMC13730232
AB  - Ferroptosis, an emerging mechanism of cell death, provides new targets for the treatment of triple-negative breast cancer (TNBC). Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, is a promising therapeutic target for TNBC. Given that GPX4 is often considered “undruggable”, proteolysis targeting chimeras (PROTACs) offer a powerful means for its degradation. However, conventional PROTACs often face challenges in achieving precise localization and potent activation in vivo. Herein, we engineered a peptide-based nano-PROTAC, named CMVG, which couples VHL- and GPX4-binding peptides with iron-based metal–organic frameworks via a “click” reaction and loads the photosensitizer chlorin e6 (Ce6). CMVG enhances ferroptosis through a dual mechanism: it degrades GPX4 via its PROTAC function to initiate ferroptosis, while generating reactive oxygen species under laser irradiation to mediate photodynamic therapy, thereby intensifying oxidative stress and accelerating ferroptosis. Furthermore, the ferroptosis induced by CMVG is highly immunogenic, triggering immunogenic cell death and reshaping the tumor immune microenvironment, ultimately boosting the anti-TNBC immune response. Additionally, CMVG exhibits excellent targeting and biocompatibility, enabling MRI-guided tumor treatment. This work presents the first peptide-based nano-PROTAC for GPX4 degradation, overcoming major limitations of conventional PROTACs, and offers a promising integrated strategy for treating TNBC.
SN  - 2211-3835
SN  - 2211-3843
ER  -