Abstract: Excessive cardiac fibrosis impairs cardiac repair after myocardial infarction (MI). In this work, an injectable composite hydrogel integrating natural biomaterials, exosomes, and bioactive molecules is developed to prevent or alleviate cardiac fibrosis. Curcumin, a natural molecule with antifibrotic activity, is encapsulated in the exosomes that are isolated from bone marrow-derived mesenchymal stem cells to enhance its water solubility and bioavailability. These composite exosomes are efficiently internalised by fibroblasts and effectively inhibit their transition to myofibroblasts in vitro. Decellularized porcine cardiac extracellular matrix (dECM) hydrogel is used as the carrier for delivering these composite exosomes to the infarcted myocardium, not only improving the retention of exosomes but also providing mechanical support and structural protection. Injection of this hydrogel into the infarcted heart of a mouse MI model leads to a decrease in collagen deposition, alleviation of fibrosis, a reduction in infarct size, and an improvement in cardiac function. The reported composite hydrogel comprising natural materials and biomolecules exhibits good biocompatibility and bioactivity. Altogether, this study demonstrates that the dECM hydrogel is a suitable platform for the local delivery of antifibrotic biomolecule-encapsulating exosomes to prevent myocardial fibrosis after MI and have great potential for the treatment of MI in clinical settings.

Key words: Myocardial fibrosis, Myocardial infarction, Decellularized extracellular matrix, Exosomes, Curcumin