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. Challenges.pdf
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