Engineering Approaches to Modify Immunomodulatory Functions of Mesenchymal Stromal Cells (MSCs): Tissue Regeneration and Clinical Application

ABSTRACT By virtue of their intrinsic immunomodulatory properties, mesenchymal stromal cells (MSCs) represent a promising therapeutic tool for immune‐related disorders. Research findings support that MSCs are involved in complex inflammatory pathologies by interacting with local immune cells. In addition to their immunomodulation ability, MSCs also contribute to cell‐mediated tissue regeneration due to their potential for multilineage differentiation. However, despite their accessibility, clinical translation of MSCs faces challenges, including their inherent heterogeneity, transient therapeutic effects, and microenvironment‐dependent functionality. This review provides an overview of current advances in MSC‐based therapies for immune‐related disorders, emphasizing Phase III and IV clinical trials and therapies approved by global regulatory agencies. Additionally, we highlight innovative engineering strategies designed to address the limitations of MSCs while enhancing their immunomodulatory capabilities. These approaches include: (1) cell pre‐treatment and genetic modification to improve therapeutic efficacy; (2) biomaterial‐mediated delivery systems for targeted sites; (3) MSC‐derived extracellular vesicle (EV)‐based therapeutics to amplify paracrine signaling; (4) induced pluripotent stem cell (iPSC)‐derived MSCs to overcome donor variability. By integrating these methodologies with ongoing clinical approaches, this review underscores the potential of engineered MSC immunomodulation in addressing inflammatory pathologies, bridging the gap between basic research and clinical application.