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 1O2 generation ability during photodynamic therapy (PDT). Meanwhile, the released Cu2+ reacts to glutathione (GSH) to generate Cu+, which provides an extra chemodynamic therapy (CDT) function through Fenton-like reactions with overexpressed H2O2, 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.