Redox Homeostasis Disruptors Based on Metal‐Phenolic Network Nanoparticles for Chemo/Chemodynamic Synergistic Tumor Therapy through Activating Apoptosis and Cuproptosis

Abstract

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal‐phenolic network nanoparticles (NPs) self‐assembled from copper ions and gallic acid (Cu‐GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu‐GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu+ and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton‐like reaction of released Cu+, which disrupts redox homeostasis and achieves apoptosis‐related chemodynamic therapy. Moreover, massive accumulation of Cu+ in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S‐acetyltransferase and downregulation of iron‐sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu‐GA NPs. The experiments in vivo further demonstrate that Cu‐GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu‐based metal‐phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.

Facile Synthesis of Basic Copper Carbonate Nanosheets for Photoacoustic Imaging-Guided Tumor Apoptosis and Ferroptosis and the Extension Exploration of the Synthesis Method

“…Cu 2+ could consume GSH and be converted into Cu + to act as a Fenton-like agent. Compared with Fe (suitable pH range: pH 2.0–4.0), Cu + -mediated Fenton-like reactions have a wider suitable pH range, exhibiting high Fenton-like activity in a slightly acidic environment. − The depletion of GSH was detected using 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB) as a probe. It can be discovered that the peak of the probe decreased dramatically with reaction time, proving that Cu 2+ -caused GSH depletion (Figure e).…”

Cuproptosis: Harnessing Transition Metal for Cancer Therapy

“…Once inside cancer cells, the GOx is activated by the overexpression of GSH, leading to a reduction in GSH levels and glucose exhaustion, ultimately inducing cuproptosis . When copper ions are delivered using gallic acid-based metal-phenolic network nanoparticles, the release of gallic acid also contributes to reducing intracellular glutathione levels . Using buthionine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase, to block glutathione synthesis is also a viable approach .…”

“…123 When copper ions are delivered using gallic acid-based metal-phenolic network nanoparticles, the release of gallic acid also contributes to reducing intracellular glutathione levels. 153 Using buthionine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase, to block glutathione synthesis is also a viable approach. 152 The previously mentioned BSO-CAT@MOF-199@DDM, as well as the nanomedicine CuET designed by Lu et al, utilize this strategy to decrease GSH levels and subsequently promote cuproptosis.…”

“…154 As mentioned earlier, although there is no direct association between ROS and the cuproptosis mechanism, it still plays a significant role in other mechanisms of copper-induced cell death, which should not be disregarded. A variety of therapeutic modalities, including radiotherapy, 155,156 PDT, 157 chemodynamic therapy (CDT), 153 and sonodynamic therapy (SDT), 158 have been demonstrated that they can kill tumor cells by producing much more ROS. These therapeutic strategies hold great potential for synergistically inducing cuproptosis and eliminating tumor cells.…”

Mild‐Photothermal Effect Induced High Efficiency Ferroptosis‐Boosted‐Cuproptosis Based on Cu2O@Mn3Cu3O8 Nanozyme

“…[9] GSHOx-like activity decomposes overexpressed intercellular GSH in tumor cells, [10] thus enhancing copper toxicity by effectively inhibiting the chelation of copper ions by GSH. [11] Moreover, GSH depletion inactivates glutathione peroxidase 4 (GPX4), thereby upregulating lethal lipid peroxidation (LPO) and reactive oxygen species (ROS), [12] which eventually induces ferroptosis. The generation of hydroxyl radicals (•OH) is augmented by catalyzing the decomposition of highly expressed hydrogen peroxide (H 2 O 2 ) in the TME via PODlike activity, [13] which further consumes GSH, thereby enhancing copper toxicity and ferroptosis.…”