Active-targeting biomimetic nanosystem for prostate cancer enhances radiotherapy efficacy by inducing ferroptosis

  • J Nanobiotechnology. 2025 Nov 30;24(1):9. doi: 10.1186/s12951-025-03879-w.
Zhihao Hu  1 ,  Hongji Li  1 ,  Kai Gan  1 ,  Yu Li  2 ,  Yao Jiang  3 ,  Keying Zhang  1 ,  Zhengxuan Li  1 ,  Yike Zhou  1 ,  Tong Lu  1 ,  Chao Xu  1 ,  Shaojie Liu  1 ,  Limin He  1 ,  Fa Yang  1 ,  Jun Jiang  1 ,  Hongtao Song  1 ,  Ying Wang  1 ,  Li Guo  4 ,  Changhong Shi  5 ,  Weihong Wen  6 ,  Donghui Han  7 ,  Weijun Qin  8
Affiliations
  • 1. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
  • 2. Department of Urology, Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 3. Department of Urology, Air Force 986 Hospital, Xi'an, 710054, China.
  • 4. The Tenth Outpatient Department, Air Force 986 Hospital, Xi'an, 710054, China.
  • 5. Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, Xi'an, 710032, China.
  • 6. Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China. [email protected].
  • 7. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. [email protected].
  • 8. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. [email protected].
PMID: 41318491 DOI: 10.1186/s12951-025-03879-w
Abstract

Radioresistance and off-target toxicity remain major challenges in prostate Cancer (PCa) radiotherapy. Here, we report a biomimetic nanoplatform (Au/MOF-FIN@M-gy1) that synergistically enhances radiation deposition and Ferroptosis for precision radiosensitization. By engineering macrophage membranes with prostate-specific membrane antigen (PSMA)-targeting nanobodies (gy1), we achieve tumor-selective delivery of Au/MOF nanoparticles preloaded with Ferroptosis inducers (FINs). Upon lysosomal release, FINs disrupt redox homeostasis via GPX4 suppression, while Au/MOF amplifies radiation-induced Reactive Oxygen Species (ROS), collectively triggering lethal lipid peroxidation cascades. This dual mechanism is further demonstrated to elicit radiosensitizing effects in both bone-metastatic and radio-refractory PCa models without requiring radiation dose escalation, thereby improving the therapeutic index. Our study demonstrates a nanoparticle-enabled strategy to enhance tumor-specific radiotherapy by dual-targeting metabolic vulnerabilities.

Keywords
Ferroptosis; Membrane-coated nanoparticles; Prostate cancer; Prostate-specific membrane antigen; Radiation therapy; Targeted therapy.
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