Abstract
Delivery of genes, including plasmid DNAs, short interfering RNAs (siRNAs), and messenger RNAs (mRNAs), using artificial non-viral nanotherapeutics is a promising approach in cancer gene therapy. However, multiple physiological barriers upon systemic administration remain a key challenge in clinical translation of anti-cancer gene therapeutics. Besides extracellular barriers including sequestration of gene delivery nanoparticles from the bloodstream by resident organ-specific macrophages, and their poor extravasation and tissue penetration in tumors, overcoming intracellular barriers is also necessary for successful delivery of nucleic acids. Whereas for RNA delivery the endosomal barrier holds a key importance, transfer of DNA cargo additionally requires translocation into the nucleus. Better understanding of crossing membrane barriers by nucleic acid nanoformulations is essential to the improvement of current non-viral carriers. This review aims to summarize relevant literature on intracellular trafficking of non-viral nanoparticles and determine key factors toward surmounting intracellular barriers. Moreover, recent data allowed us to propose new interpretations of current hypotheses of endosomal escape mechanisms of nucleic acid nanoformulations.
Highlights
Cancer gene therapy remains a significant challenge due to numerous barriers limiting delivery of genetic cargo
The membranes of early endosomal compartments are enriched with phosphatidylinositol 3-phosphate (PI3P), which provides interaction of the vesicle with cytosolic early endosome antigen 1 (EEA1), an endosomal sorting complex required for transport (ESCRT) machinery, and Rab5 GTPase (Bohdanowicz and Grinstein, 2013)
It cannot be excluded that nanoparticle internalization in a complex with some of the mentioned receptors might decrease the rate of the recycling process via the exocytosis pathway, which was reported for non-targeted lipid nanoparticles (Sahay et al, 2013) and polyplexes (Gonçalves et al, 2004)
Summary
Cancer gene therapy remains a significant challenge due to numerous barriers limiting delivery of genetic cargo. Despite advantages of viral vectors in terms of gene delivery efficacy, their use may cause immune responses and severe side effects (Raper et al, 2003; Manno et al, 2006; Howe et al, 2008) resulting in limited and very cautious clinical use In this context, synthetic carriers able to form complexes with nucleic acids, and protect them from extra- and intracellular nucleases, are considered an alternative to viral vectors. Development of cationic polymers and lipids with their ability to deliver genetic material into cells gave rise to extensive studies of the mechanisms underlying transfection properties of these carriers This knowledge would provide the basis for future improvement of their efficacy to the level comparable with viral counterparts. Parallel consideration of these data and the endosome maturation process allowed us to propose our interpretation of endosomal escape mechanisms for nucleic acid nanoformulations
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