Helper-Polymer Based Five-Element Nanoparticles (FNPs) for Lung-Specific mRNA Delivery with Long-Term Stability after...

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery Systems

Background:

• Therapeutic messenger RNA (mRNA) delivery faces challenges due to the instability of traditional lipid nanoparticles (LNPs).
• Current mRNA-LNPs require cold storage, limiting their widespread clinical application for lung diseases.
• Lung-associated diseases like viral infections, tumors, and genetic disorders represent significant unmet medical needs.

Purpose of the Study:

• To develop a novel, stable, and lung-specific mRNA delivery platform.
• To overcome the storage limitations of conventional mRNA-LNPs.
• To enhance the efficiency and specificity of mRNA delivery for treating lung diseases.

Main Methods:

• Development of five-element nanoparticles (FNPs) using a combination of helper-polymer poly(β-amino esters) (PBAEs) and DOTAP.
• Investigation of structure-activity relationships (SAR) of PBAEs, focusing on end-caps, polymerization degree, and alkyl side chain length.
• Assessment of FNP stability, including storage at 4 °C for at least 6 months after lyophilization.

Main Results:

• FNPs demonstrated enhanced stability through increased charge repulsion and improved binding forces within nanoparticles.
• PBAEs with E1 end-caps, higher polymerization degrees, and longer alkyl chains showed superior performance.
• Lyophilized FNP formulations maintained stability for over 6 months at 4 °C.

Conclusions:

• A novel FNP platform offers high efficiency, specificity, and stability for mRNA delivery to the lungs.
• This platform addresses the critical storage instability issue of traditional mRNA-LNPs.
• FNPs represent a promising advancement for mRNA-based therapeutics targeting lung-associated diseases.