UCNPs@Ce6-based Near-Infrared photodynamic therapy triggers mitophagy-related apoptosis in esophageal squamous cell carcinoma

This upconversion nanoprobe shifts Er 3+ emission from 540 to 660 nm for efficient Ce6 excitation. • First report that Ce6-loaded upconversion nanoparticles are excellent biocompatible and target ESCC cells. • The UCNPs@Ce6 platform dually functions: with PDT, ROS‑mitophagy/apoptosis alone, autophagy‑mediated anti‑inflammation. 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. Download: Download high-res image (151KB) Download: Download full-size image