Progress and prospects: the use of 3D spheroid model as a relevant way to study and optimize DNA electrotransfer.

The use of electrotransfer to deliver therapeutic agents such as cytotoxic drugs and nucleic acids to cells and tissues has been successfully developed over the last decade. This strategy is promising for the systemic secretion of therapeutic proteins, vaccination and gene therapy. The safe and efficient use of this physical method for clinical purposes requires knowledge of the mechanisms underlying the DNA electrotransfer and expression phenomena. Despite the fact that the pioneering work on plasmid DNA electrotransfer to cells was initiated 30 years ago, many of the underlying mechanisms remain elucidated. While efficient in vitro, the method faces a lack of efficiency in packed tissues. Until now, the great majority of studies have been performed on cells in 2D cultures in Petri dishes or in suspension. However, these studies cannot get access to the tissue-specific architecture and organization present in 3D living tissues. In this context, 3D cell culture models are more relevant concerning in vivo cell organization since cell-cell contacts are present as well as extracellular matrix. The aim of this review is to describe the relevance of using spheroid as a model to address and improve the electrotransfer processes.