Cascading reactive oxygen species storm amplification via a soft X-ray-activated dual-photosensitizer nanoplatform for efficient photodynamic therapy.

Conventional photodynamic therapy (PDT) is limited by the tissue penetration depth of visible light. In contrast, traditional X-ray-induced photodynamic therapy (X-PDT) may cause collateral X-ray damage to healthy tissues. To address these challenges, this study presents an innovative heterojunction nanoplatform that produces reactive oxygen species (ROS) via dual photosensitizers upon soft X-ray excitation. The platform is built around a lanthanide-doped nanoscintillator core, NaLuF:Tb/Gd(15 %/5 %)@NaYF (SNPs), which efficiently converts absorbed soft X-ray energy into visible light. The porous structure of the porphyrin-based zirconium metal-organic framework (Zr-MOF) encapsulates carbon dots (CDs) as a photosensitizer, allowing for efficient fluorescence resonance energy transfer (FRET) from SNPs to CDs through nanoscale spatial confinement. Importantly, Zr-MOF itself acts as a secondary photosensitizer, synergizing with CDs to significantly enhance ROS production. In vitro and in vivo experiments demonstrate that under low-dose soft X-ray irradiation, this platform effectively penetrates 2 cm of tissue while "cascade-amplifying" ROS generation. This enhances oxidative stress within tumor cells, inducing mitochondrial dysfunction and DNA damage. The synergistic effects promote tumor cell apoptosis and suppress breast cancer growth, demonstrating high X-PDT efficacy and biosafety. This study not only highlights the potential of combining lanthanide scintillators with metal-organic frameworks (MOFs) and CDs, but also provides a novel, highly effective, and safe therapeutic strategy for breast cancer. It overcomes the tissue penetration limitations of PDT and significantly broadens the biomedical applicability of soft X-rays.