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Review
. 2024 Sep 18;16(18):2629.
doi: 10.3390/polym16182629.

Polymers as Efficient Non-Viral Gene Delivery Vectors: The Role of the Chemical and Physical Architecture of Macromolecules

Majad Khan  1   2   3
Affiliations
Review

Polymers as Efficient Non-Viral Gene Delivery Vectors: The Role of the Chemical and Physical Architecture of Macromolecules

Majad Khan. Polymers (Basel). .

Abstract

Gene therapy is the technique of inserting foreign genetic elements into host cells to achieve a therapeutic effect. Although gene therapy was initially formulated as a potential remedy for specific genetic problems, it currently offers solutions for many diseases with varying inheritance patterns and acquired diseases. There are two major groups of vectors for gene therapy: viral vector gene therapy and non-viral vector gene therapy. This review examines the role of a macromolecule's chemical and physical architecture in non-viral gene delivery, including their design and synthesis. Polymers can boost circulation, improve delivery, and control cargo release through various methods. The prominent examples discussed include poly-L-lysine, polyethyleneimine, comb polymers, brush polymers, and star polymers, as well as hydrogels and natural polymers and their modifications. While significant progress has been made, challenges still exist in gene stabilization, targeting specificity, and cellular uptake. Overcoming cytotoxicity, improving delivery efficiency, and utilizing natural polymers and hybrid systems are vital factors for prospects. This comprehensive review provides an illuminating overview of the field, guiding the way toward innovative non-viral-based gene delivery solutions.

Keywords: DNA complexation; brush polymers; comb polymers; dendrimer; gene delivery; hydrogels; hyperbranched polymers; linear polymers; natural polymers; non-viral vectors; poly(ethylene imine); poly-L-lysine; star polymers.

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Conflict of interest statement

The author declares no conflicts of interest.

Figures

Figure 1
Figure 1
Classification of common gene delivery methods [23].
Figure 2
Figure 2
Benefits of non-viral gene delivery systems.
Figure 3
Figure 3
Mechanism of non-viral gene delivery systems [29].
Figure 4
Figure 4
Physical methods for non-viral gene delivery [43].
Figure 5
Figure 5
Chemical structure of linear poly-L-lysine (PLL).
Figure 6
Figure 6
Structure of linear PEI.
Scheme 1
Scheme 1
The synthetic approach for P (MAC-co-DTC)-g-PEI copolymers.
Figure 7
Figure 7
Structure of branched PEI.
Scheme 2
Scheme 2
Illustration of the synthesis of folate-targeted and PEG-modified HPEI (FA-PEG-HPEI) (A,B), preparation of Fe3O4 nanocarriers (NCs) within FA-PEG-HPEI (B–D), and their subsequent magnetofection study (E) [78].
Figure 8
Figure 8
Synthesis of highly branched PβAE [83].
Figure 9
Figure 9
The highly symmetrical physical architecture of the dendrimer mimics a snowflake—that is capable of featuring a unique electron-carrying path within an encapsulated π-conjugated system [87].
Figure 10
Figure 10
Dendritic structure of PAMAM [91].
Figure 11
Figure 11
Standard cores—(A) 1,4-diaminobutane(ethylenediamine), (B) ammonia, (C) cystamine and G0 PAMAM derivatives of each core [90].
Figure 12
Figure 12
PEGylation is one strategy for decreasing PAMAM toxicity [110].
Figure 13
Figure 13
Typical chemical structures of comb polymers comprised of hydrophobic backbone with oligolysine pendent groups [114].
Figure 14
Figure 14
Schematic of comb polymer synthesis with PLA side chains via the macromonomer approach. (A) Surface-initiated polymerization of the macromonomer. (B) Use of a macroCTA for macromonomer polymerization, followed by NiPAm chain extension, forming a palm tree-like structure. (C) Copolymerization of different macromonomers to produce heterografted comb polymers [116].
Figure 15
Figure 15
Chemical structure of PLL-grafted-PEG.
Scheme 3
Scheme 3
Chemical structure of the poly-cationic brush, preparation of doxorubicin-loaded nanoparticles (DOX-NPs), and multifunctional DOX-NPs/pDNA complexes [139].
Figure 16
Figure 16
Arm-first synthesis of a star-shaped polymer that employs the use of double styrene-functionalized tetraphenylethene displaying aggregation-induced emission (AIE) traits as the core and polystyrene, polyethylene, or polyethylene-b-polycaprolactone as the arms (A–E) [151].
Figure 17
Figure 17
Synthesis of star PEI-g-PAE via the grafting-onto approach for gene delivery [155].
Figure 18
Figure 18
Illustrates hydrogel use in vivo. This mesoporous polymer can encapsulate nanoparticles with target genes, forming a film at room temperature. The hydrogel film can treat flexor tendon damage [161].
Figure 19
Figure 19
Chemical structures of commonly used natural polymers for gene delivery [173].
Figure 20
Figure 20
Chemical structure of HA polymers [173].
Figure 21
Figure 21
(A) RBCs enhance therapeutic circulation and target the spleen through uptake by splenic macrophages or dendritic cells. (B) Cells such as leukocytes, stem cells, and platelets migrate to specific tissues, enabling targeted co-delivery of therapeutics [240].
Figure 22
Figure 22
Preparation process of NP/pZNF580/RBCs and their gene delivery by crossing extracellular and intracellular barriers [267].
See this image and copyright information in PMC

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This research received no external funding.

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