Delivery of transcription factors as modulators of cell differentiation

Fundamental studies performed during the last decades have shown that cell fate is much more plastic than previously considered, and technologies for its manipulation are a keystone for many new tissue regeneration therapies. Transcription factors (TFs) are DNA-binding proteins that control gene expression, and they have critical roles in the control of cell fate and other cellular behavior. TF-based therapies have much medical potential, but their use as drugs depends on the development of suitable delivery technologies that can help them reach their action site inside of the cells. TFs can be used either as proteins or encoded in polynucleotides. When used in protein form, many TFs require to be associated to a cell-penetrating peptide or another transduction domain. As polynucleotides, they can be delivered either by viral carriers or by non-viral systems such as polyplexes and lipoplexes. TF-based therapies have extensively shown their potential to solve many tissue-engineering problems, including bone, cartilage and cardiac regeneration. Yet, their use has expanded beyond regenerative medicine to other prominent disease areas such as cancer therapy and immunomodulation. This review summarizes some of the delivery options for effective TF-based therapies and their current main applications. Graphical Abstract