Upconversion Nanoparticles‐Based Multimodal Tumor Therapy Integrating Photoclick‐Induced Aggregation of Gold Nanoparticles and Ceria‐Curcumin Redox Modulation With Inflammation Attenuation Post‐Treatment

ABSTRACT A multifunctional nanoplatform (USiCeCurAu) has been developed that integrates upconversion nanoparticles (UCNPs), gold nanoparticles (AuNPs), cerium oxide (CeO 2 ), and a thioketal‐curcumin‐triphenylphosphonium conjugate (TK‐CUR‐TPP) to enable synergistic tumor therapy via photodynamic (PDT), chemodynamic (CDT), and mild photothermal therapy (mPTT). In this strategy, AuNPs attached to the surface serve as a “pore locker”, cloaking CeO 2 and CUR before entering tumor cells. UCNPs convert near‐infrared (NIR) light into UV and visible light emission, simultaneously initiating AuNP aggregation via photoclick chemistry, CeO 2 ‐mediated reactive oxygen species (ROS) generation, and TPP‐CUR‐driven PDT. The CeO 2 amplifies oxidative stress by depleting glutathione (GSH) and catalyzing ROS production (O 2 · − and ·OH), while releasing oxygen to relieve tumor hypoxia. The release of TPP‐CUR not merely resumes the negativity of the surface, but also disrupts mitochondrial function and downregulates heat shock proteins (HSPs), further sensitizing tumor cells to mPTT (∼45°C) performed by light‐induced AuNP aggregation after detachment due to electrostatic repulsion. Importantly, ROS‐scavenging ability post‐PTT of CeO 2 has been demonstrated to effectively mitigate excessive inflammation and prevent severe scab formation. This fully integrated, light‐ and ROS‐responsive nanoplatform affords significant therapeutic efficacy in 4T1 tumor‐bearing BALB/c mice, reducing tumor volume from 185 to 27 mm 3 following a single tail‐vein injection.