Challenges in DNA Delivery and Recent Advances in Multifunctional Polymeric DNA Delivery Systems

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 DNA-based 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-l-lysine (PLL), and chitosan and offer perspectives on future developments.

Tracking the DNA complexation state of pBAE polyplexes in cells with super resolution microscopy

“…DOTAP, 6 DOPE, 7 and DC-Chol 8 ), polyplexes (e.g. poly(ethyleneimine) 9 and poly(lysine) 10 ) and inorganic carriers (e.g. gold nanoparticles).…”

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials

“…to reduce the nonspecific interaction with serum components and to evade RES clearance, iii) efficient cellular uptake of the vectors by specific cancer cells via passive and/or active targeting, iv) intracellular trafficking from cell membranes to endo/lysosomes, followed by the rapid endosomal escape to avoid enzymatic degradation of genes, v) disassembly of vectors to release gene cargo for efficient transfection, and vi) transportation of nucleic acids to specific intracellular locations, such as cytoplasm (for mRNA, siRNA, miRNA, etc.) and nuclei (for plasmid DNA), where the newly introduced genome exactly works . As such, nucleic acids can be delivered at the right site of action and give rise to accurate gene expression at appropriate levels.…”

Switchable conformational changes of DNA nanogel shells containing disulfide–DNA hybrids for controlled drug release and efficient anticancer action

“…They can be made of pure DNA [19][20][21][22] or DNA combined with other components. [23][24][25][26][27] It has been shown, that DNA nanogels can reveal the resistance to nuclease degradation, enhanced cellular uptake, and more effective drug-or siRNA delivery to cancer cells. Recently, it was shown, that CpG-rich oligonucleotide layers merged with nanoparticles act as a nanoimmunotherapeutic and introduce a robust antitumor immunity through a multi-pronged mechanism of neuroblastoma.…”

“…Structural changes of graed aptamers were studied on solid-and polyelectrolyte microcapsules and linear polymeric hydrogels, where the single and duplex DNA species can be separated and can specically interact with drug molecules. 27 Thanks to the presence of DNA crosslinkers in the so nanogel network it was possible to get modulation of reversible phase transition of the hydrogel lattices for the achievement of selective drug binding and prolonged and controlled release of drugs. 31,32 Herein, we report on the development of a biocompatible, multi-responsive DNA nanogel containing specic disulde oligonucleotide-based co-crosslinkers for highly efficient loading and triggered, switchable drug release.…”