2. Academic Validation
  3. Low-dose X-ray-activated radiodynamic therapy via a lutetium-coordinated nanoplatform synergizing PARP inhibition and ferroptosis

Low-dose X-ray-activated radiodynamic therapy via a lutetium-coordinated nanoplatform synergizing PARP inhibition and ferroptosis

  • J Nanobiotechnology. 2026 Jan 16;24(1):148. doi: 10.1186/s12951-026-04027-8.
Wanli Song # 1 2,  Chuanyi Zhao # 1 2,  Youqing Mai # 1 2,  Guangrong Zhang 1 2,  Wenyue Kang 1 2,  Xuanjun Zheng 1 2,  Qingpeng Yuan 1 2,  Zeyang Chen 1 2,  Chengxun Zhong 1 2,  Junbao Tang 1 2,  Duoyi Fu 1 2,  Tiantian Zhai 1,  Kai Ling 3 4 5,  Hongyan Jiang 6 7 8
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China.
  • 2 Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China.
  • 3 Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China. [email protected].
  • 4 Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China. [email protected].
  • 5 Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China. [email protected].
  • 6 Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, 515041, China. [email protected].
  • 7 Department of Pharmacology, Shantou University Medical College, Shantou, 515041, China. [email protected].
  • 8 Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China. [email protected].
  • # Contributed equally.
PMID: 41546023 DOI: 10.1186/s12951-026-04027-8
Abstract

Low-dose X-ray-activated radiodynamic therapy (RDT) is a promising strategy for precision oncology. However, its therapeutic efficacy is limited by tumor radioresistance and insufficient generation of Reactive Oxygen Species (ROS). Here, we describe a biomimetic lutetium-coordinated black phosphorus nanosheet platform (BPNS@Lu3+/Lap-CMV) capable of initiating a tripartite synthetic lethality cascade upon low-dose irradiation. Through a single coordination strategy utilizing high atomic number (high-Z) Lu3+ ions, the nanoplatform simultaneously stabilizes the black phosphorus scaffold, functions as an efficient X-ray antenna, and integrates a pH-responsive gate for the controlled release of β-lapachone (Lap). Additionally, surface camouflage using Cancer cell membrane vesicles (CMV) enables homologous tumor targeting and reduces clearance by the reticuloendothelial system. A multi-pathway therapeutic cascade is initiated upon exposure to low-dose X-ray. First, Lu3+-amplified RDT generates a burst of ROS. Second, tumor-overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) bioactivates Lap, intensifying redox stress (GSH depletion and H2O2 overproduction) and promoting Ferroptosis. Third, co-administration of the PARP Inhibitor olaparib (Ola) functionally impairs PARP-mediated DNA repair, thereby converting RDT-induced DNA lesions into lethal damage and promoting Apoptosis. Guided by its intrinsic computed tomography-mediated visibility, which revealed peak tumor accumulation at 12 h post-administration, the triple‑combination regimen achieved 85.5% tumor suppression in an orthotopic triple-negative breast Cancer model without evident toxicity. This study presents a strategic framework for an intelligent nanoplatform capable of converting low-dose physical energy into biological cascades, thereby systematically disrupting parallel tumor defense mechanisms and broadening the therapeutic scope of radiotherapy.

Keywords

Black phosphorus; Ferroptosis; High-Z metal elements; Radiodynamic therapy; Reactive oxygen species.

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