Injectable Chito-oligosaccharide-hyaluronic Acid Hydrogels with Fe3+/AMP Nano-Enzyme Promote ROS Scavenging and Immunomodulation for Myocardial Infarction Repair.

INTRODUCTION:The post-infarction microenvironment, dominated by oxidative stress, hypoxia, and dysregulated inflammation, severely limits cardiac regeneration. Existing injectable hydrogels for myocardial infarction (MI) rarely address these factors simultaneously, and excessive reactive oxygen species (ROS) scavenging may paradoxically cause oxidative damage. OBJECTIVES:To develop an injectable hydrogel capable of concurrently scavenging ROS, sustaining oxygen release, and modulating immune responses without inducing oxidative damage. METHODS:A chitosan oligosaccharide-hyaluronic acid hydrogel (C-COS-OHA) was synthesized, incorporating a mild Fe3+/adenosine monophosphate (AMP) nano-enzyme for oxygen generation and redox stability. Carboxyl-modified chitosan oligosaccharide (C-COS) was designed to promote M2 macrophage polarization. The hydrogel was evaluated in vitro for oxidative stress protection and hypoxia tolerance, and in MI mouse models for oxygen retention, inflammation modulation, and cardiac repair. RESULTS:Compared with catalase (CAT)-loaded hydrogels, C-COS-OHA-Fe3+/AMP enhanced HUVEC survival by 28.9% under oxidative stress and accelerated scratch closure by 26.9% under hypoxia. In vivo, photoacoustic imaging confirmed prolonged oxygen retention; qRT-PCR revealed a 4.1-fold increase in TGF-β expression. After 28  days, MI mice showed 49% reduced fibrosis, 37% thicker ventricular walls, and improved left ventricular ejection fraction (58.3 ± 3.1%), all exceeding C-COS-OHA-CAT performance. CONCLUSION:The C-COS-OHA-Fe3++/AMP hydrogel integrates ROS scavenging, oxygen modulation, and immunoregulation into a single injectable platform, representing a shift from single-mechanism MI hydrogels to comprehensive microenvironmental regulation for enhanced cardiac regeneration.