Redox-responsive nanomedicine beyond glutathione: harnessing reactive oxygen species and emerging endogenous triggers for precision drug delivery.

Redox-responsive nanomedicine has emerged as a promising approach for site-selective drug delivery by leveraging pathological redox imbalances. Nevertheless, the majority of systems predominantly depend on glutathione (GSH) as a universal trigger, an assumption that frequently fails to account for the complexity and heterogeneity of endogenous redox biology across various diseases. This review critically evaluates redox-responsive nanomedicine beyond GSH, emphasizing emerging endogenous redox triggers such as reactive oxygen species (ROS), thioredoxin systems, NADPH-dependent pathways, hypoxia, and disease-specific oxidative signatures. We discuss advancements in redox-responsive chemistries, logic-gated and multi-trigger nanocarrier designs, and disease-adapted delivery strategies across oncology, inflammatory, metabolic, cardiovascular, and neurodegenerative disorders. Importantly, we analyze translational bottlenecks responsible for bench-to-bedside attrition and propose design principles to enhance biological relevance, safety, and clinical success. By integrating redox biology with nanocarrier engineering, this review outlines a roadmap toward precision redox-responsive drug delivery.