Engineering Oxidative Stress for Precision Therapy: Reactive Oxygen Species-Responsive Hydrogel-Nanocarrier Systems as Translational Redox Drug-Delivery Platforms

Abstract Reactive oxygen species (ROS) are regulated chemical signals that become pathological when production exceeds antioxidant buffering. This duality creates a translational drug-delivery opportunity: therapeutic systems can be engineered to remain stable under basal redox conditions while activating in oxidatively stressed tissues. This Review critically evaluates ROS-responsive hydrogel–nanocarrier systems as multiscale platforms for localized redox therapy. The discussion is organized around quantitative and clinically relevant design logic rather than broad cataloging. We first define hydrogels, nanocarriers, redox therapy, and hybrid hydrogel–nanocarrier systems for pharmacology, drug-delivery, and materials-science readers. We then compare physiological and pathological ROS ranges, common ROS measurement methods, and the in vitro conditions typically used to test hydrogel responsiveness. Responsive chemistries, including thioketals, aryl boronates, thioethers, disulfides, selenium/tellurium motifs, catechol/polydopamine systems, and nanozyme components, are connected to material outcomes such as degradation, swelling, self-healing, cargo release, catalytic ROS conversion, and tissue adhesion. Primary literature examples are used to link polymer composition, nanocarrier type, payload, route of administration, ROS assay, and therapeutic end point across chronic wounds, infection, cancer, myocardial injury, neural injury, and osteoarthritis. The Review concludes with translational considerations for manufacturability, sterilization, storage stability, biosafety, regulatory classification, and clinically realistic validation. Overall, progress in ROS-responsive therapeutics will depend on matching disease-specific redox biology with chemically validated, quantitatively benchmarked, and pharmacologically meaningful material design.