Design approaches of single-atom nanozymes for oxidative stress modulation: Mechanistic comprehensions, and...

Oxidative stress arises from a disturbance in redox homeostasis, where excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) overwhelms endogenous antioxidant defence mechanisms that maintain cellular redox homeostasis. Constant redox disorder is currently identified as a combined molecular mechanism causing neurodegenerative and neurological disorders, cancer progression, ischemia-reperfusion injury, chronic inflammation, and metabolic syndromes. While natural antioxidant enzymes competently normalise ROS under biological circumstances, their therapeutic transformation is hindered by structural fragility, immunogenicity, compromised activity in complex biological conditions, and high costs of manufacturing. Nanozymes have been developed as strong catalytic nanomaterials capable of replicating enzyme-like functions, but traditional strategies suffer from low catalytic selectivity, heterogeneous active sites, and limited atom utilisation and efficiency. Single-atom nanozymes (SAzymes) overcome these limitations by stabilising single metal atoms inside well-defined coordination designs; SAzymes accomplish maximal atomic distribution, perfect electronic modulation, and enzyme-mimetic active sites that mimic natural metalloenzymes at the atomic level. This structural accuracy enables higher catalytic kinetics, improved substrate specificity, and the ability to tailor pathological microenvironments through programmable redox functions. This review provides a comprehensive overview of molecular basis of oxidative stress and progress in redox regulation approaches, followed by state-of-the-art synthesis methods and atomic-scale characterisation techniques for SAzymes. Their multienzyme-like activities in fine-tuning ROS dynamics are critically evaluated. Moreover, emerging therapeutic uses in neuroprotection, ischemia-reperfusion management, cancer, metabolic diseases, and inflammatory disorders are thoroughly reviewed, emphasising mechanistic understandings, design inventions, and translational limitations that define the next frontier of single-atom nanozyme-associated precision medicine.