X-ray/Hypoxia-Activated Nanoplatform for Cascade-Amplified Combination Therapy of Orthotopic Glioblastoma

X-ray-induced photodynamic therapy (X-PDT), with deep tissue penetration capability, offers a promising therapeutic strategy for glioblastoma (GBM), but its therapeutic efficacy is limited by the poor stability of organic photosensitizers and the low radioluminescence efficiency of scintillators. To solve these issues, we constructed a nanoplatform using the organolanthanide scintillator Eu(TTA)3phen as an X-ray energy harvester and zinc-doped CoMo-LDH (ZCM-LDH) as a photosensitizer. After further modification with lactoferrin (LF) and loading of the hypoxia-activated prodrug TH302, the resulting ZCM-LDH@Eu/T-LF efficiently inhibited GBM growth through the synergistic effect of X-PDT and hypoxia-activated chemotherapy. Benefiting from the strong X-ray absorption capacity and efficient exciton utilization of Eu(TTA)3phen, together with the excellent photostability of the photosensitizer ZCM-LDH, ZCM-LDH@Eu/T-LF achieved highly efficient production of singlet oxygen (1O2) under X-ray excitation. Furthermore, the combination of X-PDT and hypoxia-activated prodrug TH302 achieved effective GBM treatment by inducing mitochondrial dysfunction, oxidative membrane damage, and DNA damage, thus offering an efficient strategy for GBM therapy.