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Review
. 2025 May 1:20:5613-5643.
doi: 10.2147/IJN.S515734. eCollection 2025.

Removing Barriers to Tumor 'Oxygenation': Depleting Glutathione Nanozymes in Cancer Therapy

Ruilong Sun  1   2   3 , Ruitang Liu  1   2 , Yongzheng Tian  1 , Yunfei Li  1 , Bo Fan  1 , Songkai Li  1
Affiliations
Review

Removing Barriers to Tumor 'Oxygenation': Depleting Glutathione Nanozymes in Cancer Therapy

Ruilong Sun et al. Int J Nanomedicine. .

Abstract

Nanozymes are nanomaterials capable of mimicking natural enzyme catalysis in the complex biological environment of the human body. Due to their good stability and strong catalytic properties, nanozymes are widely used in various fields of biomedicine. Among them, nanozymes that trigger intracellular reactive oxygen species (ROS) levels for cancer therapy have gained significant attention. However, the 'explosion' of ROS in tumor cells was prevented by the high levels of glutathione (GSH) in the tumor microenvironment (TME). GSH, a prominent endogenous antioxidant, increases the resistance of tumor cells to oxidative stress by scavenging ROS. Certain nanozymes can deplete intracellular GSH levels by mimicking GSH oxidase (GSHOx), GSH peroxidase (GPx) or by interfering with the reduction of oxidized glutathione (GSSG). On the one hand, elevated the level of intracellular ROS and induced lipid peroxidation reaction leading to ferroptosis. On the other hand, it creates favorable conditions for the treatment of tumors with photodynamic therapy (PDT), sonodynamic therapy (SDT), chemodynamical therapy (CDT) and targeted therapy. In this paper, we present a comprehensive analysis of GSH-depleting nanozymes reported in recent years, including classification, mechanism, responsiveness to TME and their roles in cancer therapy, and look forward to future applications and developments.

Keywords: cancer therapy; enzyme mimetic; glutathione depletion; nanomaterials; nanozymes; oxygen-dependent therapy.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Article Structure. (By Figdraw) Four aspects of GSH-depleting nanozymes are presented: background, classification, TME responsiveness, and ODCT.
Figure 2
Figure 2
Catalytic schematic of nanozymes mimicking OXD, POD, SOD, CAT. (By Figdraw) Where S represents the substrate and P represents the product.
Figure 3
Figure 3
Principle of GSH Detection by DTNB. (By Figdraw).
Figure 4
Figure 4
The nanozymes release metal ions, causing GSH depletion as well as ROS accumulation. (By Figdraw).
Figure 5
Figure 5
AuPt@Cu-PDA NPs with photothermal conversion effect were synthesized by Liu et al (By Figdraw).
Figure 6
Figure 6
Under US, BCNR oxidized GSH and inhibited GR, ultimately leading to iron death. (By Figdraw).
See this image and copyright information in PMC

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