A multifunctional nanoplatform (USiCeCurAu) has been developed that integrates upconversion nanoparticles (UCNPs), gold nanoparticles (AuNPs), cerium oxide (CeO2), 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 CeO2 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, CeO2-mediated reactive oxygen species (ROS) generation, and TPP-CUR-driven PDT. The CeO2 amplifies oxidative stress by depleting glutathione (GSH) and catalyzing ROS production (O2·− 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 CeO2 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 mm3 following a single tail-vein injection.
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