Nanomedical approaches to deplete intracellular glutathione in oncology

Abstract

Glutathione (GSH) plays a critical role in maintaining redox homeostasis and conferring chemoresistance to cancer cells, making it an attractive target for therapeutic intervention. Recent advances in nanomedicine have led to the development of diverse nanostructures capable of depleting GSH, either stoichiometrically or catalytically. These systems exploit the elevated GSH demand in tumors to selectively disrupt redox balance, enhancing reactive oxygen species (ROS) accumulation and improving the efficacy of conventional therapies. Approaches include metal-based nanocatalysts, GSH-responsive prodrugs, and stimuli-activated platforms using light or ultrasound for spatiotemporal control. Despite promising preclinical outcomes, key challenges remain, including limited mechanistic understanding, variability in GSH sensitivity across cancer types, and a lack of standardized assays to evaluate GSH-depleting efficiency. Addressing these gaps will require cross-disciplinary efforts bridging materials science, chemical biology, and catalysis. Such integration is essential for translating GSH-targeting nanomedicines into effective clinical tools against drug-resistant malignancies. This perspective provides an overview of some of the most promising nanomaterials explored in the current state of the art and discusses the main strategies and challenges relevant to future clinical translation.