Engineering Multi-Functional Enzyme-Mimetic Polyphenol-Catalase Complex for Reversing Hypoxia and Redox Homeostasis in Vascular and Muscular Regeneration.

Abstract

Hypoxia contributes to a wide range of pathological conditions, including muscle atrophy and ischemic diseases, yet effective therapeutic strategies remain limited. In this study, we developed an epigallocatechin-3-gallate (EGCG)-catalase complex (EC) that simultaneously provides oxygenation and reactive oxygen species (ROS) clearance through multienzyme mimicry. EC exhibits superoxide dismutase (SOD)-like activity by converting superoxide anion (O₂^•-) into hydrogen peroxide (H₂O₂), followed by catalase-mediated decomposition of H₂O₂ into oxygen (O₂) and water (H₂O), thereby transforming harmful ROS into beneficial O₂. In addition, EC employs peroxidase (POD)- and glutathione peroxidase (GPx)-like pathways to further eliminate residual H₂O₂, establishing a cascade antioxidative defense system. At the cellular level, EC modulated hypoxia-inducible factor-1 alpha (HIF-1α) expression, promoted angiogenesis, and enhanced myogenic differentiation. <i>In vivo</i>, EC improved muscle regeneration and functional recovery in a dexamethasone-induced atrophy model, while promoting angiogenesis and suppressing fibrosis in a diabetic hindlimb ischemia model. Collectively, these findings highlight EC as an integrated therapeutic platform that combines O₂ supply with ROS regulation via multienzyme mimicry, offering promising potential for the treatment of hypoxia-associated diseases.