Engineering Metal-Organic Framework Hybrid AIEgens with Tumor-Activated Accumulation and Emission for the Image-Guided GSH Depletion ROS Therapy.

Aggregation-induced emission (AIE)-active luminogens (AIEgens) have demonstrated exciting potential for the application in cancer phototheranostics. However, simultaneously achieving tumor-activated bright emission, enhanced reactive oxygen species (ROS) generation, high tumor accumulation, and minimized ROS depletion remains challenging. Here, a metal-organic framework (MOF) hybrid AIEgen theranostic platform is designed, termed A-NUiO@DCDA@ZIF-Cu, composed of an AIEgen-loaded hydrophobic UiO-66 (A-NUiO@DCDA) core and a Cu-doped hydrophilic ZIF-8 (ZIF-Cu) shell. The fluorescence emission and therapeutic ROS activity of AIEgens are restrained during delivery. After uptake by tumor tissues, ZIF-Cu decomposition occurs in response to an acidic tumor microenvironment (TME), and the hydrophobic A-NUiO@DCDA cores self-assemble into large particles, extremely increasing the tumor accumulation of AIEgens. This results in enhanced fluorescence imaging (FLI) and highly improved O generation ability during photodynamic therapy (PDT). Meanwhile, the released Cu reacts to glutathione (GSH) to generate Cu, which provides an extra chemodynamic therapy (CDT) function through Fenton-like reactions with overexpressed HO, resulting in the GSH depletion-enhanced ROS therapy. As a result of these characteristics, the MOF hybrid AIEgens can selectively kill tumors with excellent efficacy.