Injectable pH Responsive Conductive Hydrogel for Intelligent Delivery of Metformin and Exosomes to Enhance Cardiac Repair after Myocardial Ischemia‐Reperfusion Injury

Myocardial ischemia-reperfusion injury (MIRI) is a leading cause of complications and high mortality associated with acute myocardial infarction. Injectable hydrogel emerges as a promising biomaterial for myocardial repair due to their ability to mimic the mechanical and electrophysiological properties of heart tissue. In this study, an injectable conductive hydrogel is developed that responds to the weakly acidic microenvironment of ischemic injury, enabling the intelligent release of metformin and exosomes to enhance cardiac repair following MIRI. This multifunctional hydrogel demonstrates self-healing properties, shear-thinning injectability, electrical conductivity, and an elastic modulus comparable to natural myocardium, alongside excellent biocompatibility. At the cellular level, the hydrogel system exhibits significant antioxidant, anti-apoptotic, improvement of electrophysiological characteristics, mitochondrial protection and angiogenic effects, with transcriptome sequencing revealing the effective activation of the PI3K/AKT, VEGF, and AMPK signaling pathways. In vivo studies further confirm that the hydrogel treatment reduces infarct size, cardiac fibrosis and incidence of arrhythmia, while improving ventricular ejection fraction and facilitating the restoration of cardiac function after MIRI. In conclusion, an injectable pH-responsive conductive hydrogel is presented that enables the intelligent delivery of metformin and exosomes, offering a promising and novel therapeutic approach for enhancing cardiac repair and treating MIRI.