Genetic Modifications of MSCs to Improve Therapeutic Efficacy

Human mesenchymal stem/stromal cells (MSCs) have attracted significant interest in regenerative medicine due to their self-renewal capacity, immunomodulatory functions, multipotency, and relative ease of isolation and expansion. However, several limitations restrict their clinical application, including cellular heterogeneity, challenges in large-scale expansion, and poor in vivo persistence after transplantation. Systemically administered MSCs are rapidly cleared because of limited adhesion, short survival time, and inefficient extravasation, resulting in suboptimal therapeutic efficacy. To overcome these challenges, various strategies have been developed, such as hypoxic preconditioning, biomaterial-based approaches, and genetic modification. Among these, genetic modification represents a particularly powerful and versatile strategy, as it enables targeted enhancement of specific functional properties of MSCs and even the introduction of novel therapeutic capabilities. In this review, we summarize recent advances in genetically engineered MSCs and categorize these approaches into four functional domains: migration, adhesion, secretion, and survival. We further discuss their therapeutic outcomes across diverse disease models in vivo. Collectively, genetic modification substantially enhances the intrinsic therapeutic potential of MSCs and represents a promising direction for the development of next-generation cell-based therapies.