Engineering boronic acid-integrated lipid nanoparticles for precision glycan-mediated gene transfer

Area of Science:

• Biotechnology
• Nanomedicine
• Gene Therapy

Background:

• Aberrant cell-surface glycosylation is an underexplored target for selective gene delivery.
• Tocopherol-based cationic gemini lipids offer a foundation for novel nanocarrier development.

Purpose of the Study:

• To engineer boronic acid-functionalized tocopherol lipids for glycan-targeted gene delivery.
• To evaluate the efficacy and selectivity of these novel nanocarriers in cancer cells.

Main Methods:

• Integration of phenylboronic acid (TNB) and pyridinylboronic acid (TNBPY) into tocopherol-based gemini lipid formulations (DOPE-TH8S).
• Characterization of co-liposomal nanoparticles for DNA complexation (zeta potential, ethidium bromide assay, gel electrophoresis).
• In vitro transfection studies in cancer (4T1, MCF-7) and non-cancerous (McCoy, MCF-10A) cell lines, including blocking experiments.

Main Results:

• Stable co-liposomal nanoparticles demonstrated strong pDNA complexation.
• Exceptional EGFP transfection efficiency in cancer cells at an ultralow N/P ratio (2), outperforming Lipofectamine 2000.
• Phenylboronic acid formulation (TNB) showed superior transfection compared to pyridinylboronic acid (TNBPY).
• Targeted uptake via sialic acid pathway confirmed by blocking experiments.
• High cancer-cell selectivity with negligible transfection in non-cancerous cells.

Conclusions:

• Phenyl- and pyridinylboronic acid-functionalized tocopherol lipids represent a new class of programmable glycan-targeting nanocarriers.
• Reversible boronate-sialic acid interactions enable potent, cancer-selective gene transfer.
• These engineered systems hold significant potential for next-generation targeted gene therapeutics.