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. 2020 Mar;3(3):1900206.
doi: 10.1002/adtp.201900206. Epub 2020 Feb 13.

Non-cationic Material Design for Nucleic Acid Delivery

Ziwen Jiang  1 , S Thayumanavan  1
Affiliations

Non-cationic Material Design for Nucleic Acid Delivery

Ziwen Jiang et al. Adv Ther (Weinh). 2020 Mar.

Abstract

Nucleic acid delivery provides effective options to control intracellular gene expression and protein production. Efficient delivery of nucleic acid typically requires delivery vehicles to facilitate the entry of nucleic acid into cells. Among non-viral delivery vehicles, cationic materials are favored because of their high loading capacity of nucleic acids and prominent cellular uptake efficiency through electrostatic interaction. However, cationic moieties at high dosage tend to induce severe cytotoxicity due to the interference on cell membrane integrity. In contrast, non-cationic materials present alternative delivery approaches with less safety concerns than cationic materials. In this Progress Report, principles of non-cationic material design for nucleic acid delivery are discussed. Examples of such non-cationic platforms are highlighted, including complexation or conjugation with nucleic acids and self-assembled nucleic acid structures.

Keywords: Nucleic acid delivery; material design; non-cationic; non-viral.

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Figures

Figure 1.
Figure 1.
Schematic illustration of poly(ethylene glycol) shielding cationic moieties. (a) The poly(L-lysine) block was partially thiolated, initiating the complexation with plasmid DNA via electrostatic interaction as well as crosslinking the complex with disulfide linkage. PEG-b-PLL, poly(ethylene glycol)-poly(L-lysine) block copolymers. Adapted with permission.[21] Copyright 2004, American Chemical Society. (b) Hydrophobic anticancer drug was used to electrostatically complex with siRNA, followed by an encapsulation step using PEG-b-PLA block copolymers. PEG-b-PLA, poly(ethylene glycol)-polylactide block copolymers. Adapted with permission.[22] Copyright 2019, American Chemical Society.
Figure 2.
Figure 2.
Schematic illustration of plasmid DNA-cationic polypeptide polyelectrolytes with hyaluronic acid (HA) coating. Cellular uptake process of HA-coated complexes: (a) Binding with cell surface CD44 receptor; (b~c) Endocytosis; (d) Disruption of endosomal membrane by cationic polypeptide and subsequent release of content. Adapted with permission.[26] Copyright 2016, American Chemical Society.
Figure 3.
Figure 3.
(a) Complexation between plasmid DNA and dipicolylamine-containing polymer through Zn(II) coordination. DPA, dipicolylamine. Adapted with permission.[31] Copyright 2018, American Chemical Society. (b) Complexation between siRNA and anionic mesoporous silica nanoparticle through their interaction with Ca2+ ion. MSN, mesoporous silica nanoparticle. Adapted with permission.[34] Copyright 2019, Elsevier Ltd.
Figure 4.
Figure 4.
Scheme of non-cationic crosslinked polymer for RNA complexation. DTT, dithiothreitol. Adapted with permission.[44] Copyright 2019, American Chemical Society.
Figure 5.
Figure 5.
Small molecule modifications are generally designed on the 3’-end of the siRNA sense strand. (a) Molecular design of representative lipid-conjugated siRNAs. Adapted with permission.[55] Copyright 2007, Springer Nature. (b) Schematic illustration of triantennary N-acetylgalactosamine-conjugated siRNA. GalNAc, N-acetylgalactosamine. Adapted with permission.[57] Copyright 2014, American Chemical Society.
Figure 6.
Figure 6.
Polymer-conjugated nucleic acid via the click reaction between dibenzocyclooctyne (DBCO) and azide. (a) Conjugation between DBCO-functionalized RNA and azide-containing block copolymer. Adapted with permission.[62b] Copyright 2019, American Association for the Advancement of Science. (b) Formulation process of the hybridized complex between siRNA and DNA-grafted-polycaprolactone (PCL) (DNA-g-PCL). Before the hybridization step, DBCO-functionalized DNA was first conjugated with azide-decorated PCL. Adapted with permission.[64] Copyright 2018, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 7.
Figure 7.
Synthesis of nucleic acid-gold nanoparticle conjugates. Adapted with permission.[67a] Copyright 2012, American Chemical Society.
Figure 8.
Figure 8.
(a) One-step self-assembly of oligonucleotide nanoparticles. Six single-stranded DNA altogether self-assemble into tetrahedral structure. Arrowhead stands for the 5’-end of each DNA strand, with each color corresponding to one of the six edges of the tetrahedron. Meanwhile, the design allows site-specific hybridization of siRNA to the tetrahedron edge. (b) Atomic force microscopy image of the tetrahedral oligonucleotide nanoparticles. (c) Folic acid (FA) density on the oligonucleotide nanoparticle affects the GFP gene silencing efficiency of the particle. LF, Lipofectamine RNAiMAX formulated with siGFP (siRNA of GFP). 0, 1, 2, 3, or 6 FA represent oligonucleotide nanoparticles with same siGFP concentration and varied number of folic acid. *P < 0.003, **P < 0.001 compared with control (siGFP only). NS, not significant. Adapted with permission.[74] Copyright 2012, Springer Nature.
Figure 9.
Figure 9.
Schematic illustration of rolling circle amplification-assisted DNA assembly for CpG oligodeoxynucleotide (CpG ODN) and anti-PD-1 antibody (aPD1) delivery. (a) CpG-sequence containing DNA assembly was loaded with aPD1 and caged restriction enzyme. Under inflammation condition, proteolytic enzyme degrades triglycerol monostearate (TGMS) and releases the restriction enzyme, triggering the fragmentation of DNA assembly. As a result, CpG ODN and aPD1 are released at the inflammation site. (b) With aPD1 for PD 1 blockade, released CpG ODN activates dendritic cells (DCs) to drive T cell response, enhancing the immune response against cancer cells. Adapted with permission.[81] Copyright 2016, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 10.
Figure 10.
Schematic representation of aptamer-siRNA chimeric structure. Reproduced with permission.[92] Copyright 2011, American Association for the Advancement of Science.
Figure 11.
Figure 11.
(a) Schematic comparison between membrane fusion and endocytosis using liposomes as the delivery vehicle. Adapted with permission.[122] Copyright 2011, American Chemical Society. (b) Confocal microscopy images of siRNA delivery via membrane fusion process. After the delivery, Cy5-labeled siRNAs are homogenously distributed in the cytosol of most cells. The scale bar represents 20 μm. Adapted with permission.[123] Copyright 2018, Elsevier Ltd. (c) Confocal microscopy images of the cellular internalization of DNA via endocytosis. When Cy3-labeled DNA overlaps with the Lysotracker Green (a fluorescent stain for cellular lysosomes), it is denoted in yellow and represents the endosomal entrapment of DNA. The scale bars represent 10 μm Adapted with permission.[110] Copyright 2015, American Chemical Society.
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