Doping Engineering Inspired Calcium Fluoride Nanozymes With Multifunctional Oxidative Storm for Enhanced Radio-Catalytic Therapy.

Radiotherapy, particularly radio-catalytic therapy, demonstrates immense potential in eliciting anti-tumor effects. However, its efficacy is substantially constrained by the low energy conversion efficiency of x-rays, limited reactive oxygen species (ROS) generation pathways, and the hypoxia-induced radio-resistance within the tumor microenvironment. Herein, we developed a spherical Cu/Lu/Tb co-doped CaF2 nanozyme coated with hyaluronic acid (CLTC@HA), which simultaneously exhibits highly efficient energy conversion and multifunctional catalytic activities, enabling a synergistically enhanced radio-catalytic therapy through doping engineering. The collaborative interplay of Cu/Lu/Tb ions enables precise control over the crystal lattice, leading to tailored morphology and modulated bandgap in CLTC@HA, consequently enhancing its radio-sensitization efficacy. CLTC@HA reveals multicatalytic activity through intrinsic peroxidase (POD)-like activity of CaF2 crystal, co-doping enhanced radio-catalytic property, and Cu-mediated redox cycle. Crucially, the introduced Cu+/Cu2+ valence cycle efficiently depletes glutathione and promotes hydroxyl radical production via POD-like activity. Consequently, CLTC@HA provokes a severe redox imbalance, effectively reversing the hypoxic radio-resistance and ultimately achieving superior anti-tumor efficacy. Notably, the optimal treatment group reaches a tumor growth inhibition rate of 99.1%. Furthermore, benefiting from abundant high-Z elements, CLTC@HA exhibits prominent T1-weighted imaging capability. This work presents a promising one-component nanoplatform for advanced radio-catalytic therapy and preclinical imaging.