A microenvironment-responsive, injectable, and conductive hydrogel integrated with a catalytic nanozyme with ROS scavenging, anti-inflammation, and pro-angiogenic capabilities for synergistic myocardial infarction therapy.

Abstract

Myocardial infarction (MI) often leads to adverse ventricular remodeling, a major precursor to heart failure, while current clinical approaches remain limited in effectively promoting myocardial regeneration and suppressing fibrosis. To address these challenges, we developed an injectable, smart-responsive hydrogel integrated with catalytic nanozyme and conductive components for synergistic MI repair. The hydrogel is constructed using phenylboronic acid-modified oxidized hyaluronic acid (OHA-PBA) and dopamine-grafted gelatin (GelDA) as the backbone, cross-linked via dynamic Schiff base and boronate ester bonds, conferring rapid self-healing and specific MI microenvironment-responsive properties. This biomimetic network not only replicates the structure and function of the native extracellular matrix but also responds specifically to the acidic and highly reactive oxygen species (ROS) microenvironment within the infarcted zone, enabling on-demand drug release. Incorporated into the hydrogel are black phosphorus nanosheets (BP Ns) to restore electrical conductivity, and puerarin-loaded honeycomb-like manganese dioxide nanozymes (PHMP NPs) that act as both ROS scavengers and in situ oxygen generators. Together, these components work synergistically to promote angiogenesis, alleviate local hypoxia, and reestablish blood and oxygen supply to the ischemic tissue. This integrated platform thus concurrently delivers mechanical support, restores electrical signaling, alleviates hypoxia, and combines antioxidant, anti-inflammatory, pro-angiogenic, and anti-fibrotic capabilities, offering a comprehensive multi-target therapeutic strategy for MI. Both in vitro and in vivo evaluations demonstrate that the developed hydrogel can effectively inhibit pathological ventricular remodeling, enhance vascularization, and modulate inflammatory responses, with histopathological and transcriptomic analyses further confirming these therapeutic effects, thereby significantly promoting the recovery of cardiac functions and offering a promising and advanced therapeutic strategy for MI treatment. STATEMENT OF SIGNIFICANCE: This work presents an injectable hydrogel platform that uniquely integrates electrical conductivity, catalytic oxygen generation, and smart microenvironment responsiveness for myocardial infarction (MI) therapy. Its significance lies in overcoming the limitation of current single-target approaches by enabling a synergistic multi-functional therapy. The system simultaneously restores electrical conduction, scavenges reactive oxygen species, alleviates hypoxia, and inhibits fibrosis within the infarcted heart. This integrated biomaterial strategy establishes a new paradigm for addressing the complex pathophysiology of MI, offering broad interest to researchers in biomaterials science, cardiac tissue engineering, and regenerative medicine.