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Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) production has been envisioned as an effective cancer treatment. However, the efficacy is limited by the hypoxia, insufficient hydrogen peroxide conversion, and high glutathione (GSH) levels in the tumor microenvironment (TME). To solve these issues, we proposed and designed a biocompatible, oxygen resistant Cu-modified Ti 3 C 2  nanocomposite (Ti 3 C 2 -Cu-PEG), which can efficiently deplete the endogenous GSH in tumor cells, smartly respond to NIR-II light irradiation with in-depth tissue penetration to achieve photothermally enhanced tumor photodynamic therapy (PDT) and catalytic therapy. Specifically, Ti 3 C 2 -Cu-PEG reacted with oxygen to produce singlet oxygen ( 1 O 2 ) under NIR-II irradiation, and catalyzed the highly expressed H 2 O 2  in the tumor microenvironment to generate ·OH. In addition, Ti 3 C 2 -Cu-PEG significantly decreased intracellular GSH, reduced the chances of reaction between ROS and GSH, and thus promoting ROS effect. Moreover, the intrinsically high photothermal conversion efficiency of Ti 3 C 2 -Cu-PEG further promotes the NDT process.  In vitro  and  in vivo  experiments, the Ti 3 C 2 -Cu-PEG nanosystem showed excellent antitumor effect in 4T1 tumor-bearing mice by amplifying oxidative stress under NIR-II stimulation. This work highlights an easily synergistic nanosystem with remodeling TME and combined photothermal therapy to enhance the therapeutic effect of NDT in tumor therapy.

Copper decorated Ti 3 C 2 nanosystem with NIR-II-induced GSH-depletion and reactive oxygen species generation for efficient nanodynamic therapy