The mesenchymal stromal cell (MSCs) secretome, comprising growth factors, cytokines, chemokines, and extracellular vesicles (exosomes), has emerged as a promising cell-free therapeutic approach in regenerative medicine. This review highlights recent advancements in integrating the MSC secretome with biomaterial scaffolds for drug delivery and tissue repair. The secretome's paracrine signaling promotes tissue regeneration, offering advantages over traditional cell-based therapies by reducing immune risks and enhancing scalability. Scaffold systems such as hydrogels, electrospun nanofibers, and 3D-printed constructs have been designed to encapsulate the MSC secretome or exosomes, enabling controlled and localized delivery. Loading strategies, including surface adsorption, hydrogel embedding, microsphere encapsulation, and lyophilization, are employed to optimise release kinetics. MSC-derived exosomes, in particular, serve as efficient nanoscale carriers, enhancing bioavailability and protecting therapeutic cargo. Preclinical studies demonstrate the efficacy of secretome-integrated scaffolds in wound healing, cartilage repair, angiogenesis, antifibrotic therapy, neuroprotection, and tumour targeting. While the approach shows strong therapeutic promise, challenges such as production standardization, batch variability, targeting specificity, and regulatory constraints remain. Ongoing research in scaffold engineering and secretome optimization is essential to overcome these barriers and support clinical translation. Overall, MSC secretome-integrated scaffolds represent a safe, effective, and scalable strategy for regenerative therapy.
