Cationic Bottlebrush Polymers Outperform Linear Polycation Analogues for pDNA Delivery and Gene Expression

Area of Science:

• Polymer Chemistry
• Biomaterials Science
• Gene Delivery Technology

Background:

• Cationic polymers are effective nonviral vectors for nucleic acid delivery due to their tunable properties.
• Synthetic polymer chemistry enables precise control over macromolecular architecture for enhanced gene delivery efficacy.

Purpose of the Study:

• To investigate the efficacy of cationic bottlebrush polymers for plasmid DNA (pDNA) delivery.
• To compare the gene delivery performance of bottlebrush polymers against their linear counterparts.

Main Methods:

• Synthesis of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA) bottlebrush polymers via ring-opening metathesis polymerization.
• Characterization of polymer properties, including toxicity and pDNA complexation (bottleplexes).
• Evaluation of pDNA delivery efficiency and gene expression (EGFP) in HEK293 cells.

Main Results:

• Bottlebrush polymers, particularly BB_37, showed up to a 60-fold increase in gene expression (%EGFP+) compared to linear polymers.
• Gene expression increased with higher polymer molecular weight.
• Bottlebrushes demonstrated superior pDNA transport to the nucleus compared to linear analogues, despite similar cellular uptake.

Conclusions:

• Cationic bottlebrush polymer architecture significantly enhances pDNA delivery and expression efficiency over linear polymers.
• Architectural modifications of polymers are crucial for optimizing biomacromolecule delivery vehicles.
• Bottlebrush polymers show great potential as advanced nonviral gene delivery systems.