Hypoxia-Regulating Nanozymes for Biomedicine

Hypoxic microenvironments arise when local oxygen supply fails to meet cellular demand and exert an influence on the progression of cancer, ischemic heart and brain injury, chronic inflammatory disorders, and other diseases. Conventional approaches, including oxygen delivery systems, small-molecule redox drugs, and natural enzymes, can relieve hypoxia but suffer from poor tissue specificity, short duration of action, and limited stability. Nanozymes are engineered nanomaterials with enzyme-like catalytic activity. Through controllable redox reactions, they can regulate oxygen generation or consumption, rebalance reactive oxygen species, and reprogram hypoxic microenvironments at the cellular and tissue levels. In recent years, the field has shifted from empirical trial-and-error to rational nanozyme design, with a focus on defined active sites, disease-responsive activity, and targeted delivery. Herein, we summarize the key design principles governing nanozyme catalytic performance and discuss the catalytic mechanisms involved in hypoxia regulation. We then examine how distinct pathological features of acute and chronic hypoxic microenvironments create different catalytic requirements and how nanozyme functions can be tailored accordingly. Furthermore, we provide an overview of nanozyme applications across hypoxia-associated diseases and discuss emerging opportunities and barriers for clinical translation. This review is expected to provide insights for developing precise and clinically valuable hypoxia-regulating nanozymes.