• This rare earth up-conversion nanoparticle platform overcomes the characteristic of Er 3+ that its highest fluorescence emission peak is at 540 nm under 980 nm laser excitation, with the highest fluorescence emission peak near 660 nm for better exciting Ce6. • It is confirmed for the first time that the chlorin e6-loaded up-conversion nanoparticle platform has excellent biocompatibility and efficient tumor-targeting ability in esophageal squamous cell carcinoma cells. • Chlorin e6-loaded up-conversion nanoparticle platform has a dual regulatory function. First, its combination with photodynamic therapy activates mitochondrial apoptosis and mitochondrial autophagy related to reactive oxygen species. Second, this nanoplatform itself may suppress the inflammatory pathway by activating autophagy. Chlorin e6 (Ce6), an efficient photosensitizer, suffers from poor biocompatibility, and lanthanide-doped upconversion nanoparticles (UCNPs) possess unique optical properties, yet their roles in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, Ce6-loaded UCNPs (UCNPs@Ce6) with a core–shell-shell structure was designed and synthesized to overcome the limitation of conventional photodynamic therapy (PDT) that relies on shallow-penetrating light. In vitro, UCNPs@Ce6-PDT selectively inhibited ESCC cells without affecting normal esophageal epithelial cells. Mechanistically, PDT induced mitochondrial dysfunction, mitophagy, and apoptosis via the reactive oxygen species (ROS)-mitochondrial pathway, whereas UCNPs@Ce6 alone activated autophagy and inhibited pyroptosis/necroptosis-related inflammation. In vivo, the fluorescence image-guided tumor therapy achieved tumor growth inhibition (73.72% ± 2.88%) without obvious toxicity. Collectively, this nanoplatform provides a safe and effective strategy for targeted therapy of ESCC by combining PDT-triggered mitophagy-related apoptosis with autophagy-mediated anti-inflammatory responses.
Chen et al. (2026) studied this question.