<p>Stem cells play a crucial role in tissue repair, not only by differentiating into progeny that directly replace damaged tissues, but also by secreting diverse factors that support host regeneration. Among these regenerative signals, extracellular vesicles released by stem cells (SC-EVs) have emerged as key mediators of intercellular communication. SC-EVs contribute to tissue repair by delivering their molecular cargo to recipient cells, modulating signaling pathways, metabolic processes, and gene expression. Recent findings suggest that various extracellular proteins dynamically associate with the EV surface, forming a context-dependent layer known as the protein corona. The protein corona interacts with cell-surface receptors and promotes the targeted uptake of SC-EVs, thereby enhancing their therapeutic potential. In this review, we explore the molecular mechanisms underlying the formation of the protein corona and highlight its unique roles in modulating SC-EVs to regulate aging processes, promote regeneration, and maintain tissue homeostasis. We also discuss emerging strategies to engineer the protein corona of SC-EVs through surface cargo modulation, aimed at enhancing their therapeutic potential. This review offers novel insights into the protein corona of SC-EVs as a modulable nanoplatform for their application. A deeper understanding of its properties will be crucial for optimizing cell-free therapies, opening new avenues for advancing regenerative medicine.</p> Graphical Abstract <p></p>