Tumor microenvironment-responsive MIL-53(Fe)@MnO2- induced glutathione depletion and sustained hydroxyl radical generation for enhanced chemodynamic cancer therapy

Abstract

The design of nanomedicines targeting specific tumor microenvironment (TME) characteristics, such as low pH, hypoxia, and elevated glutathione (GSH) concentration, holds significant potential for selectively killing cancer cells. In this study, we have developed a TME-responsive nanoparticle, i.e., MIL-53(Fe)@MnO₂ stabilized with polyethylene glycol (FMP), which is capable of depleting GSH and sustainably generating hydroxyl radical (•OH) for enhanced chemodynamic therapy of cancer. After endocytosis, the FMP nanoparticles undergo gradual decomposition, resulting in GSH depletion while releasing Fenton-active Fe²⁺ and Mn²⁺ ions. These ions then subsequently catalyze a Fenton-like reaction to generate highly toxic •OH, ultimately inducing oxidative cell death. As a synergistic effect, the depletion of GSH further enhances therapeutic efficacy by inhibiting intracellular •OH scavenging. In vivo experiments demonstrated that this synergistically chemotherapeutic approach efficiently suppressed tumor growth without inducing significant systemic toxicity. This work presents a promising nanotherapeutic strategy that simultaneously depletes intracellular GSH and sustains cytotoxic •OH generation for enhanced tumor treatment.

Keywords: Chemodynamic therapy; Fenton-like reaction; Glutathione depletion; Hydroxyl radical generation; Tumor microenvironment responsive.