Stage-matched conductive hydrogel with pH/ROS/MMP9 triple-responsive salidroside release for post-infarction myocardial repair

Myocardial infarction (MI) triggers massive cardiomyocyte loss, inflammatory and fibrotic remodeling, and disruption of electrical conduction, which are difficult to reverse with a single therapeutic modality. Pathologically, the infarcted myocardium undergoes a sequential transition from local acidosis to oxidative/inflammatory injury and finally matrix metalloproteinase-driven scar formation. Guided by these stage-specific cues and the need to restore electrical continuity, we designed an injectable conductive hydrogel (PGO/CAM@Sal) that integrates a polypyrrole-based conductive network with pH/reactive oxygen species (ROS)/matrix metalloproteinase-9 (MMP9) triple-responsive salidroside delivery. The hydrogel matches myocardial stiffness, exhibits favorable injectability, self-healing and tissue adhesion, shows electrical conductivity comparable to native myocardium, and enables on-demand salidroside release under MI-mimicking conditions. In vitro, PGO/CAM@Sal effectively scavenges ROS, suppresses pro-inflammatory cytokine production, promotes M2 macrophage polarization and angiogenesis, and enhances connexin-43 expression and cardiomyocyte electrical coupling. In a rat MI model, local injection of PGO/CAM@Sal bridges the non-conductive infarct, stabilizes ventricular electrophysiology, improves conduction velocity and homogeneity, reduces arrhythmia vulnerability, and concurrently attenuates fibrosis, hypertrophy, and adverse left ventricular remodeling, leading to marked recovery of systolic function. Transcriptomic analysis suggests a potential involvement of the Mmp12/Cybb axis and related pathways involved in inflammation, oxidative stress, fibrosis, calcium handling, and ion transport. These molecular alterations were further validated by qRT-PCR and immunohistochemical analyses, collectively supporting the integrated therapeutic benefits observed. Accordingly, this stage-matched conductive smart hydrogel provides a comprehensive, spatiotemporally controlled strategy for precise post-MI repair.