Innovative nonviral gene delivery strategies for engineering human mesenchymal stem cell phenotypes toward clinical applications

Although human mesenchymal stem cells (hMSCs) have been used in many clinical trials, variable outcomes have resulted in no FDA-approved hMSC treatment. However, research into developing hMSC therapies for many diseases continues. An approach to manipulate hMSCs for therapeutic applications is gene delivery. Nonviral gene delivery is safer and more flexible than viral vectors, but much less efficient, especially in hMSCs. It is not understood why hMSCs are more difficult to transfect than cell lines, but innate features of hMSCs may present unique barriers to transfection. Recently, strategies to improve hMSC transfection have been developed by innovating nanocarriers, nucleic acid cargos, and by ‘priming’ hMSCs chemically and physically for more efficient transfection. These strategies aim to engineer hMSCs with new phenotypes mediated by transgenic secreted factors, receptors, transcription factors, and genome editing systems for clinical applications requiring enhanced immunomodulation and/or tissue regeneration, or for functions such as tumor-killing and tissue engineering.