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

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@Lu 3+ /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) Lu 3+ 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, Lu 3+ -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 H 2 O 2 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.