A carrier-free metal-coordinated dual-photosensitizers nanotheranostic with glutathione-depletion for fluorescence/photoacoustic imaging-guided tumor phototherapy

[Display omitted] As a promising noninvasive tumor treatment modality, dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has drawn extensive research interest in imaging-guided synergistic antitumor treatment. However, developing a high-efficient phototherapeutic agent is still a huge challenge, since single photosensitizer often suffers from the insufficient photothermal conversion efficiency (PCE) or low reactive oxygen species (ROS) productivity. Moreover, the overexpression of reductive glutathione (GSH) in tumor cells also severely compromises PDT efficiency. Here, inspired by the glutathione oxidase activity of high-valent transition metal ions, we designed a copper-coordinated nanotheranostic (PhA@NanoICG) by the coordination-driven co-assembly of photothermal-agent indocyanine green (ICG) and photodynamic-agent pheophorbide A (PhA), in which Cu2+ acted as a bridge to tightly associate ICG with PhA. Such carrier-free metal-coordinated nanotheranostics exhibited ultra-high dual-photosensitizers co-loading (~96.74 wt%) and excellent structural stability. Notably, NanoICG significantly increase the PCE of ICG via J-aggregation induced UV–vis absorption red-shift. Once PhA@NanoICG accumulated in tumor sites, they could be disassembled triggered by the weakly acidic and highly reducible tumor microenvironment. Moreover, the Cu2+ can deplete intracellular GSH and impair cellular antioxidant defense system, reducing the unnecessary ROS consumption caused by glutathione. Under fluorescence/photoacoustic imaging-guided laser irradiation, local hyperthermia and ROS were generated to induce tumor cells apoptosis. The in vitro and in vivo experiments consistently confirm that PhA@NanoICG could induce remarkable tumor inhibition through self-enhanced PTT and PDT, which may pave a new way for cancer therapy.