Near infrared excitation of an upconversion nanoparticle@TiO2-nitrate system to generate nitrate radicals for deep tissue penetration in tumor catalytic therapy

Tumor catalytic therapy is challenged by uncontrolled reaction sites and limited radical diffusion, leading to both safety concerns and insufficient therapeutic depth. Here, we develop an injectable UCNPs@TiO₂-nitrate hydrogel system that enables intratumoral, in situ generation of long-lived nitrate radicals (•NO₃, t_1/2 ≈ 60 μs) with superior diffusion capability under near-infrared (NIR) irradiation. In this system, upconversion nanoparticles convert 980 nm NIR light into ultraviolet (UV) emission, which activates TiO₂ to generate oxidative holes that catalyze NO₃^- into •NO₃. The hydrogel matrix spatially confines radical generation within the tumor site, achieving controlled and sustained release. Compared to conventional short-lived •OH systems, •NO₃ exhibits enhanced penetration and prolonged reactivity, and its combination with •OH provides synergistic oxidative damage. In vitro and in vivo results demonstrate that the dual-radical system significantly improves tumor suppression while maintaining favorable biocompatibility. This work offers a robust strategy to overcome the diffusion and safety limitations of conventional catalytic therapy by achieving spatiotemporally confined and synergistic radical generation within tumors. STATEMENT OF SIGNIFICANCE: This study introduces a hydrogel platform that converts near-infrared light into UV to activate TiO₂ and generate long-lived nitrate radicals (•NO₃) in vivo. These radicals offer extended lifetime and reactivity, allowing deeper tumor penetration compared to traditional short-lived species like •OH. The system achieves spatiotemporally controlled radical release at tumor sites, enhancing catalytic therapy precision. A dual-radical strategy combining •NO₃ and •OH further boosts therapeutic efficacy. Importantly, this approach shows minimal systemic toxicity and strong translational potential. These findings expand the reactive species toolbox and offer a promising direction for radical-based cancer therapy.