Polymeric nucleic acid carriers: current issues and novel design approaches

Abstract

To deliver nucleic acids including plasmid DNA (pDNA) and short interfering RNA (siRNA), polymeric gene carriers equipped with various functionalities have been extensively investigated. The functionalities of these polymeric vectors have been designed to overcome various extracellular and intracellular hurdles that nucleic acids and their carriers encounter during their journey from injection site to intracellular target site. This review briefly introduces known extracellular and intracellular issues of nucleic acid delivery and their solution strategies. We examine significant yet overlooked factors affecting nucleic acid delivery (e.g., microenvironmental pH, polymer/siRNA complexation, and pharmaceutical formulation) and highlight our reported approaches to solve these problems.

Fig. 1

Some examples of polycations for gene delivery

Fig. 2

Extracellular acidic pH-induced deshielding approach: (a) Formation of the layer-by-layer nanocomplex through the charge-charge interaction between DNA, polycation (PEI), and PSD-b-PEG, (b) the nanocomplex shielded at a physiological pH of 7.4 and deshielded at an acidic tumor pH of 6.6, and (c) the in vitro transfection efficiency of the nanocomplex exposed to different pH values. [35] (Reproduced with permission)

Fig. 3

Effects of medium pH on decomplexation of polyplexes. Increasing RFU (%) indicates pDNA exposure in the polyplexes.[30] (Reproduced with permission)

Fig. 4

Polymeric transfection in drug-sensitive cells (MCF7) and drug-resistant cells (MCF7/ADR-RES): (a) intracellular pH, (b) intracellular distribution, (c) cellular uptake, and (d) in vitro transfection efficiency of polyplex. [29] (Reproduced with permission)

Fig. 5

pH-tunable endosomolytic oligomeric sulfonamides (OSAs): (a) chemical structures, (b) in vitro transfection efficiency of OSA-polyplexes, (c) acid titration curve of OSAs for proton buffering capacity, and (d) aqueous solubility transition of OSAs. [27] (Reproduced with permission)

Fig. 6

PLL-based polyplexes containing siRNA and pDNA: (a) particle size of PLL/siRNA polyplex, (b) luciferase silencing efficiency of PLL/siRNA polyplex, (c) particle size and surface charge of PLL-based siRNA-pDNA polyplex, and (d) luciferase silencing efficiency of PLL-based siRNA-pDNA polyplex.[36] (Reproduced with permission)

Fig. 7

Reconstitutable (PLGA_36kDa)₂-b-bPEI micelle-based pDNA polyplex: (a) schematic representation of the structures of (PLGA_36kDa)₂-b-bPEI_25kDa micelles, micelle/pDNA complexes, and micelle/pDNA/bPEI_LMW complexes, (b) particle sizes and surface charges of micelle/pDNA complexes and micelle/pDNA/bPEI_1.8kDa complexes before and after reconstitution, (c) in vitro transfection efficiency of fresh and reconstituted micelle/pDNA/bPEI_1.8kDa complexes (1 μg of pDNA) in MCF7 cells (5×10⁵ cells seeded), and (d) pDNA-dose dependent transfection efficiency of “reconstituted” micelle/pDNA/bPEI_1.8kDa (WR 1) complexes in MCF7 cells. When using 1 μg of pDNA, its concentration was 0.5 μg/mL. [37] (Reproduced with permission)