Self-Assembled Copper–Amino Acid Nanoparticles for in Situ Glutathione “AND” H₂O₂ Sequentially Triggered Chemodynamic Therapy

TLDR

Nanoformulations that respond to tumor microenvironment cues such as weak acidity, hypoxia, and high glutathione show promise for selective cancer cell killing. This study demonstrates self‑assembled copper‑amino acid mercaptide nanoparticles that enable glutathione‑activated and H₂O₂‑reinforced chemodynamic therapy for drug‑resistant breast cancer. After endocytosis, the Cu‑Cys NPs first react with intracellular GSH, depleting it and reducing Cu²⁺ to Cu⁺, which then reacts with H₂O₂ via a Fenton‑like reaction to produce hydroxyl radicals that trigger apoptosis in the acidic tumor microenvironment. The nanoparticles exhibit selective cytotoxicity toward tumor cells while sparing normal cells, and in vivo studies show efficient inhibition of drug‑resistant breast cancer without obvious systemic toxicity, indicating strong therapeutic potential.

Abstract

Nanoformulations that can respond to the specific tumor microenvironment (TME), such as a weakly acidic pH, low oxygen, and high glutathione (GSH), show promise for killing cancer cells with minimal invasiveness and high specificity. In this study, we demonstrate self-assembled copper-amino acid mercaptide nanoparticles (Cu-Cys NPs) for in situ glutathione-activated and H2O2-reinforced chemodynamic therapy for drug-resistant breast cancer. After endocytosis into tumor cells, the Cu-Cys NPs could first react with local GSH, induce GSH depletion, and reduce Cu2+ to Cu+. Subsequently, the generated Cu+ would react with local H2O2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, which has a fast reaction rate in the weakly acidic TME, that are responsible for tumor-cell apoptosis. Due to the high GSH and H2O2 concentration in tumor cells, which sequentially triggers the redox reactions, Cu-Cys NPs exhibited relatively high cytotoxicity to cancer cells, whereas normal cells were left alive. The in vivo results also proved that Cu-Cys NPs efficiently inhibited drug-resistant breast cancer without causing obvious systemic toxicity. As a novel copper mercaptide nanoformulation responsive to the TME, these Cu-Cys NPs may have great potential in chemodynamic cancer therapy.