Engineering the oxidative myocardium: ROS-responsive biomaterials for precision cardiovascular delivery in ischemia-reperfusion injury and post-infarction remodeling

Myocardial ischemia-reperfusion injury (MIRI) and post-infarction remodeling are characterized by dynamic oxidative stress that varies across myocardial regions and disease stages. Reactive oxygen species (ROS)-responsive and redox-modulating biomaterials seek to exploit this environment through stimulus-triggered release or degradation, ROS scavenging, targeted delivery, local retention, and stage-specific repair. This review critically evaluates preclinical strategies for MIRI, myocardial infarction, and post-infarction remodeling. Major platform classes differ substantially in mechanism and translational feasibility: injectable hydrogels offer local retention and spatiotemporal control but often require invasive administration; systemic nanoparticles and liposomes enable tissue-, cell-, or organelle-level targeting but require stronger biodistribution and clearance data; nanozymes provide sustained catalytic redox activity but raise persistence and safety concerns; and cell-, nucleic-acid-, or gas-based systems introduce additional manufacturing and regulatory complexity. Mechanistically, redox interaction represents the initiating action, followed by proximal mitochondrial and cell-death regulation, inflammatory modulation, and later effects on angiogenesis, fibrosis, and ventricular remodeling. Although preclinical studies demonstrate cardioprotective and repair-promoting effects, direct cross-platform comparisons remain limited. Translation is constrained by heterogeneous models, inconsistent definitions of ROS responsiveness, incomplete pharmacokinetic and safety characterization, sparse large-animal validation, and limited manufacturing evidence. ROS-responsive cardiovascular biomaterials therefore remain promising but clinically unproven precision-delivery strategies.