Diblock Copolymer Targeted Lipid Nanoparticles: Next-Generation Nucleic Acid Delivery System Produced by Confined...

Area of Science:

• Biotechnology
• Materials Science
• Gene Therapy

Background:

• Lipid nanoparticles (LNPs) show promise for nucleic acid delivery but face challenges in extrahepatic delivery due to rapid clearance.
• The rapid desorption of lipid-polyethylene glycol (PEG) in the bloodstream limits LNP efficacy beyond the liver.

Purpose of the Study:

• To develop and optimize biodegradable block copolymer (BCP)-stabilized LNPs (BCP-LNPs) as an alternative to traditional lipid-PEG LNPs.
• To evaluate the physicochemical properties, transfection efficiency, and targeting capabilities of BCP-LNPs for nucleic acid delivery.

Main Methods:

• A Design of Experiment (DOE) approach was used to systematically optimize BCP-LNP formulations.
• Physicochemical properties, encapsulation efficiency, and transfection efficiency in HeLa and A549 cells were assessed.
• Targeted BCP-LNPs were created using Cetuximab conjugation for EGFR-overexpressing cells.

Main Results:

• Optimized BCP-LNPs demonstrated desirable physicochemical properties and high encapsulation efficiency.
• Certain BCP-LNP formulations achieved up to a 40-fold increase in transfection efficiency in HeLa cells with minimal cytotoxicity.
• Targeted BCP-LNPs showed 2.4 times higher transfection in EGFR-overexpressing A549 cells compared to non-targeted BCP-LNPs.
• BCP-LNPs proved versatile, efficiently encapsulating and delivering both mRNA and plasmid DNA (pDNA).

Conclusions:

• BCP-LNPs offer a viable and versatile platform for efficient nucleic acid delivery, overcoming limitations of traditional LNPs.
• The use of biodegradable block copolymers enhances LNP anchoring and enables improved extrahepatic and targeted delivery.
• BCP-LNPs hold significant potential for advanced gene therapy applications, particularly for challenging targets like tumors.