Macromolecular gene delivery systems: Advancing non-viral therapeutics with synthetic and natural polymers

Introduction

Gene therapy addresses genetic disorders by correcting defective genes, but delivery remains challenging. Viral vectors, while efficient, pose risks like immunogenicity and insertional mutagenesis. Non-viral macromolecular systems (e.g., polymers, lipids) offer design flexibility, scalability, and functionalization potential (Table 1). Their limitations—lower transfection efficiency and stability issues—drive ongoing optimization.

 

Natural Polymers: Biodegradable Foundations

Chitosan

• Derived from chitin, chitosan’s pH-sensitive behavior (pKa ≈6.5) enables reversible solubility transitions.

• Modifications (PEGylation, methylation) enhance polyplex stability and endosomal escape.

• Key study: PEG-chitosan nanoparticles delivered miR-33 to macrophages, modulating cholesterol metabolism.

Dextran

• Neutral polysaccharide modified with cationic groups (e.g., diethylaminoethyl dextran) for DNA binding.

• Application: Carboxymethyl-β-dextran/protamine sulfate carriers co-delivered docetaxel, chloroquine, and siRNA, suppressing triple-negative breast cancer growth.

Hyaluronic Acid (HA)

• Targets CD44 receptors overexpressed in tumors. HA’s negative charge prolongs circulation and resists degradation.

• Example: HA-chitosan nanoparticles delivered PXDN siRNA to ovarian cancer cells, inhibiting angiogenesis.

 

Synthetic Cationic Polymers: Engineered Efficiency

Poly(L-lysine) (PLL)

• Linear polypeptide modified via PEGylation to reduce cytotoxicity.

• Forms toroidal/spheroid DNA complexes; grafting onto chitosan improved transfection.

Polyethylenimine (PEI)

• High charge density enables strong DNA condensation but causes cytotoxicity.

• Innovations:

  • Cyclic amine-modified PEI reduced CXCR4-mediated tumor invasion.

  • PEI-graphene oxide composites lowered toxicity while enhancing transfection.

Poly(β-amino esters) (PBAEs)

• Biodegradable, pH-responsive, and low-toxicity.

• Outperformed PEI in plasmid DNA delivery and enabled primary cell transfection.

 

Dendritic and Specialized Architectures

Dendrimers (PAMAM)

• Hyperbranched structures with functional surfaces. High-generation dendrimers show efficiency but face cytotoxicity.

• Solution: ROS-responsive polypropylene sulfide conjugation reduced toxicity while maintaining gene delivery.

Star Polymers

• Multi-armed design improves gene loading and cellular uptake.

• Highlight: PEI-core star polymers achieved 264× higher transfection in stem cells vs. linear PEI.

Comb and Brush Polymers

• Comb polymers: Hydrophobic backbones with oligolysine "teeth" enable stable polyplexes.

• Brush polymers: PEG-based designs with disulfide linkages enhanced siRNA delivery and extended blood half-life 19-fold.

 

Targeting Strategies

Functionalization with ligands (e.g., peptides, antibodies) enables cell-specific delivery:

• RGD peptide-modified polyplexes targeted tumor integrins.

• EGF-conjugated PAMAM dendrimers selectively accumulated in EGFR+ breast tumors.

 

Limitations and Future Directions

Challenges: Cytotoxicity, batch variability, and suboptimal in vivo performance.
Future Strategies:

• Stimuli-responsive systems: pH/redox-triggered release for spatiotemporal control.

• Hybrid carriers: Blend natural polymers (chitosan, HA) with synthetic designs.

• Nanotechnology: BBB-penetrating nanoparticles for brain-targeted delivery.

 

Conclusion

Macromolecular systems bridge critical gaps in gene therapy via architectural innovation (star, brush, dendritic polymers) and smart functionalization. Future success hinges on optimizing in vivo stability, scalability, and targeted delivery—paving the way for clinically viable non-viral therapeutics.

 

Full text

https://www.xiahepublishing.com/2572-5505/JERP-2025-00009

 

The study was recently published in the Journal of Exploratory Research in Pharmacology.

Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.

 

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