Conductive bioadhesive hydrogel with controlled astragaloside IV release for ferroptosis-mediated cardiac repair.

Myocardial infarction (MI) poses significant therapeutic challenges due to the heart's limited regenerative capacity, often resulting in fibrosis, impaired electrical conduction, and adverse ventricular remodeling. To overcome these challenges, we engineered a conductive and bioadhesive hydrogel capable of controlled, sustained release of Astragaloside IV (AST), targeting ferroptosis-associated pathways to promote cardiac repair. The hydrogel was synthesized through dynamic Schiff-base crosslinking between dopamine-functionalized gelatin (GelDA) and aldehyde-modified Pluronic F127 (F127-CHO), with polydopamine-polypyrrole (PDA-PPy) nanoparticles incorporated to enhance electrical conductivity, mechanical stability, and tissue adhesion via synergistic catechol chemistry. Thermosensitive F127 micelles within the hydrogel efficiently encapsulated and delivered AST to the infarction myocardium, overcoming the bioavailability limitations of hydrophobic therapeutics. In vitro studies confirmed that AST-loaded hydrogels effectively suppressed hypoxia-induced ferroptosis in cardiomyocytes by activating the Nrf2/HO-1 pathway, substantially reducing lipid peroxidation, attenuating inflammation, and enhancing cell viability. In vivo evaluations in a rat MI model demonstrated robust myocardial adhesion, restoration of synchronized electrical conduction, reduced fibrosis, and preservation of mitochondrial integrity. Histological assessments further revealed enhanced cardiomyocyte organization, improved intercellular connectivity, and increased neovascularization, collectively contributing to functional ventricular recovery. These results underscore the therapeutic efficacy and mechanistic innovation of this multifunctional hydrogel, presenting substantial translational potential for controlled, ferroptosis-targeted cardiac repair.