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

ABSTRACT 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 CaF 2 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 CaF 2 crystal, co‐doping enhanced radio‐catalytic property, and Cu‐mediated redox cycle. Crucially, the introduced Cu + /Cu 2+ 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 T 1 ‐weighted imaging capability. This work presents a promising one‐component nanoplatform for advanced radio‐catalytic therapy and preclinical imaging.