X‐Ray‐Controlled Generation of Peroxynitrite Based on Nanosized LiLuF₄:Ce³⁺ Scintillators and their Applications for Radiosensitization

Peroxynitrite (ONOO⁻ ), the reaction product derived from nitric oxide (NO) and superoxide (O₂ -• ), is a potent oxidizing and nitrating agent that modulates complex biological processes and promotes cell death. Therefore, it can be expected that the overproduction of ONOO⁻ in tumors can be an efficient approach in cancer therapy. Herein, a multifunctional X-ray-controlled ONOO⁻ generation platform based on scintillating nanoparticles (SCNPs) and UV-responsive NO donors Roussin's black salt is reported, and consequently the mechanism of their application in enhanced therapeutic efficacy of radiotherapy is illustrated. Attributed to the radioluminescence and high X-ray-absorbing property of SCNPs, the nanocomposite can produce NO and O₂ -• simultaneously when excited by X-ray irradiation. Such simultaneous release of NO and O₂ -• ensures the efficient X-ray-controlled generation of ONOO⁻ in tumors. Meanwhile, the application of X-rays as the excitation source can achieve better penetration depth and induce radiotherapy in this nanotherapeutic platform. It is found that the X-ray-controlled ONOO⁻ -generation platform can efficiently improve the radiotherapy efficiency via directly damaging DNA, downregulating the expression of the DNA-repair enzyme, and overcoming the hypoxia-associated resistance in radiotherapy. Therefore, this SCNP-based platform may provide a new combinatorial strategy of ONOO⁻ and radiotherapy to improve cancer treatment.