Abstract

After more than 20 years of intensive  investigations, gene therapy has become one of the most  promising strategies for treating genetic diseases. However, the  lack of ideal delivery systems has limited the clinical realization  of gene therapy’s tremendous potential, especially for DNAbased  gene therapy. Over the past decade, considerable  advances have been made in the application of polymer-based  DNA delivery systems for gene therapy, especially through  multifunctional systems. The core concept behind multifunctional  polymeric DNA delivery systems is to endow one single  DNA carrier, via materials engineering and surface modification,  with several active functions, e.g., good cargo DNA  protection, excellent colloidal stability, high cellular uptake efficiency, efficient endo/lysosome escape, effective import into the  nucleus, and DNA unpacking. Such specially developed vectors would be capable of overcoming multiple barriers to the  successful delivery of DNA. In this review, we first provide a comprehensive overview of the interactions between the protein  corona and DNA vectors, the mechanisms and challenges of nonviral DNA vectors, and important concepts in the design of  DNA carriers identified via past reports on DNA delivery systems. Finally, we highlight and discuss recent advances in  multifunctional polymeric DNA delivery systems based on “off-the-shelf” polycations including polyethylenimine (PEI), poly-Llysine  (PLL), and chitosan and offer perspectives on future developments.