Metal−organic framework derived multicomponent nanoagent as a reactive oxygen species amplifier for enhanced photodynamic therapy

Intracellular antioxidants such as glutathione (GSH) play a critical role in protecting malignant tumor cells from apoptosis induced by reactive oxygen species (ROS) and in mechanisms of multidrug and radiation resistance. Herein, we rationally design two multicomponent self-assembled photodynamic therapy (PDT) nanoagents, that is, Glup-MFi-c and Glud-MFo-c, which consist of respective GSH-passivation and GSH-depletion linkers in metal−organic frameworks encapsulated with photosensitizers for a deeply comprehensive understanding of GSH-based tumor PDT. Multicomponent coordination, π−π stacking, and electrostatic interactions among metal ions, photosensitizers, and bridging linkers under the protection of a biocompatible polymer generate homogeneous nanoparticles with satisfied size, good colloid stability, and ultrahigh loading capacity. Compared to the GSH-passivated Glup-MFi-c, the GSH-depleted Glud-MFo-c shows pH-responsive release of photosensitizer and [FeIII(CN)6] linker in tumor cells to efficiently deplete intracellular GSH, thus amplifying the cell-killing efficiency of ROS and suppressing the tumor growth in vivo. This study demonstrates that Glud-MFo-c acts as a ROS amplifier, providing a useful strategy to deeply understand the role of GSH in combating cancer. Ministry of Education (MOE) National Research Foundation (NRF) Accepted version This research is supported by the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03), the Singapore Academic Research Fund (RT12/19), the National Natural Science Foundation of China (31471268), and the National Key Research and Development Program of China (Stem Cell and Translational Research, 2016YFA0101202).