Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA...

Area of Science:

• Polymer chemistry
• Nanotechnology
• Gene delivery

Background:

• Current polymer-based nucleic acid delivery systems often require complex synthesis, purification, and excipients for efficacy.
• Achieving targeted delivery, particularly to the lungs and innate immune cells, remains a challenge.
• Enhancing stability, endosomal escape, and in vivo performance are critical for clinical translation.

Purpose of the Study:

• To develop a simplified, excipient-free, single-component polymer nanoparticle platform for nucleic acid delivery.
• To achieve lung-selective gene transfection in vivo.
• To enable targeted delivery to hard-to-transfect innate immune cells.

Main Methods:

• Synthesis of a polyester-based nanoparticle platform using ionizable N-methyldiethanolamine (MDET) and hydrophobic alkyl diols (Cp).
• Formulation of polyplexes with plasmid DNA (pDNA) or messenger RNA (mRNA).
• In vivo evaluation of nanoparticle stability, serum resistance, and transfection efficiency in lung cells (alveolar macrophages, dendritic cells).

Main Results:

• The single-component, excipient-free platform demonstrated high serum and enzymatic stability.
• Polymer nanoparticles achieved lung-selective nucleic acid transfection in vivo.
• Specific formulations (Poly MDET-C4, Poly MDET-C6) mediated high protein expression in lung alveolar macrophages and dendritic cells.
• No significant tissue damage or systemic inflammatory responses were observed.

Conclusions:

• A simple, excipient-free, polyester-based nanoparticle platform enables lung-selective nucleic acid delivery.
• The platform effectively targets innate immune cells in the lungs, showing potential for genetic medicine.
• This approach simplifies production and may accelerate the clinical deployment of polymer-based genetic therapies.