The presence of a stem cell source in the epicardium that can be stimulated by exogenous delivery of transforming growth factor-β (TGF-β) and migrate towards the myocardium can represent a new approach to achieve cardiac repair following myocardial infarction. However, injection of drugs always requires use of carriers which help stabilize the compound in the harsh and dynamic environment of the heart. To this extent, pH-responsive drug delivery systems represent an enthralling approach to ensure minimal invasiveness, instantaneous responsiveness, and targeted delivery of the incorporated compound. In this in vitro study we aimed to validate an Ureidopyrimidinone-based supramolecular hydrogel as TGF-β carrier for epicardial activation. The results demonstrated the capacity of the hydrogel to respond to pH changes and deliver the growth factor, which retained its ability to activate its signalling pathway and stimulate treated cells.