pH-activatable brominated pentamethine cyanine dyes for imaging-guided photodynamic immunotherapy of tumors

Photodynamic therapy (PDT) has emerged as a minimally invasive antitumor strategy, yet conventional photosensitizers often suffer from off-target phototoxicity under physiological conditions. This study presents a novel pH-activatable brominated pentamethine cyanine dye (C-CyBr) as a smart photosensitizer for imaging-guided photodynamic therapy (PDT). A hydroxylated indole moiety was rationally introduced as the pH-sensitive switch. Under neutral physiological pH (7.4), the dye exists in a closed-ring non-fluorescent and photoinert state with negligible reactive oxygen species (ROS) generation and fluorescence emission. In contrast, once exposed to the acidic tumor microenvironment (pH ≤ 6.5, the critical activation threshold), the hydroxyl group undergoes rapid protonation, which restores the conjugated π-electron system, activates fluorescence imaging signals and simultaneously unlocks the photosensitizing activity. C-CyBr was further used to prepar nanoparticles (OCBr), which exhibit excellent tumor accumulation via the enhanced permeability and retention effect. Following tumor accumulation, the fluorescence signal of OCBr enables real-time monitoring of its biodistribution, thereby guiding the optimal timing for light irradiation. Subsequently, OCBr undergoes endocytosis into cancer cells, where the acidic lysosomal environment (pH < 5.0) triggers nanoparticle disassembly and release of the active photosensitizer. The liberated photosensitizer then escapes from lysosomes and specifically targets mitochondria, enabling localized photodynamic damage upon light irradiation. In vivo experiments reveal that OCBr-mediated PDT not only strongly inhibits tumor growth but also elicits immunogenic cell death, promoting dendritic cell maturation and CD4⁺/CD8⁺ T-cell infiltration, thereby activating a systemic antitumor immune response. OCBr serves as a promising pH-activatable theranostic platform for PDT with boosted efficacy and immunomodulatory potential.