Mesenchymal stem cells (MSCs) have garnered significant attention for their therapeutic potential, particularly in tissue regeneration and repair, because of their ability to differentiate into various cell types, secrete bioactive molecules, and modulate immune responses. Recently, there has been a shift in regenerative medicine toward secretome-based approaches that focus on paracrine factors secreted by MSCs rather than the cells themselves. This shift capitalizes on the MSC-derived secretome’s capacity to promote tissue repair, reduce inflammation, and support cell survival, offering a less invasive alternative to cell-based therapies. In the context of bone regeneration, bone morphogenetic protein-2 (BMP-2) plays a pivotal role by stimulating osteoblast differentiation, enhancing bone formation, and accelerating healing. However, BMP-2 can not be sufficiently secreted by human mesenchymal stem cells (MSCs). The insertion of the BMP-2 transgene into MSCs provides a promising strategy for producing secretomes containing BMP-2. However, expressing recombinant BMP-2 in MSCs is challenging and often leads to difficulty achieving high secretion target protein. This study aimed to review strategies to promote the expression and secretion of BMP-2 in MSCs based on selected papers from the PubMed database. Plasmid constructs are a key factor in the successful expression of recombinant proteins in mammalian cells, including BMP-2 in MSCs. This study summarized strategies for developing effective plasmid constructs, including promoter selection, enhancer addition, and coexpression with other genes © 2025 Universiti Putra Malaysia Press. All rights reserved.