Abstract
Mesenchymal stem/stromal cells (MSCs) are known for their regenerative and immunomodulatory capabilities, which have made them the focus of extensive therapeutic research. A growing body of evidence underscores that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free platform that mimics the therapeutic benefits of MSCs while mitigating their associated risks. This review synthesizes recent advancements in bioengineering strategies aimed at enhancing the therapeutic efficacy, targeting specificity, and cargo-loading capacity of MSC-EVs for cancer treatment. These strategies include endogenous and exogenous modification approaches. Endogenous strategies involve genetically modifying parental MSCs or using environmental preconditioning to modulate the extracellular vesicles (EVs) content or surface proteins of EVs they produce. Exogenous techniques include post-isolation loading of therapeutic cargo, such as small interfering RNAs (siRNAs) and microRNAs (miRNAs), as well as EV membrane modifications. We also highlight key preclinical and clinical findings, addressing the dual role of MSC-EVs, which can be either pro- or anti-tumorigenic depending on the MSC tissue origin and the tumor microenvironment. Notably, EVs derived from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) show the most consistent tumor-suppressive activity, making them a preferred choice for clinical development. Despite challenges related to production scalability, cargo-loading efficiency, and regulatory standardization, engineered MSC-EVs are poised to become a transformative platform in next-generation, cell-free precision cancer therapies. Future efforts, including the establishment of protocols compliant with Good Manufacturing Practice (GMP) and the integration of engineering advancements, will be essential for advancing healthcare innovations.