Polypeptide-engineered lipid nanoparticles for mRNA delivery with limited immunogenicity.

Area of Science:

• Biotechnology
• Nanomedicine
• Immunology

Background:

• Lipid nanoparticles (LNPs) are crucial for mRNA delivery, with polyethylene glycol (PEG) lipids influencing their properties.
• PEGylated LNPs often trigger anti-PEG antibodies, causing hypersensitivity and reduced effectiveness with repeated use.

Purpose of the Study:

• To develop and evaluate poly(D, L-serine) (pDLS) lipids as non-immunogenic alternatives to PEG lipids in LNP formulations for mRNA delivery.
• To assess the stability, efficacy, and immunogenicity of pDLS-based LNPs (pDLS-LNPs) compared to established PEG-based LNPs.

Main Methods:

• Systematic screening of pDLS lipid structures to optimize LNP formulation for stability and mRNA encapsulation.
• In vivo evaluation of pDLS-LNPs carrying SARS-CoV-2 spike mRNA in mice, assessing mRNA delivery, immune response, and toxicity.
• Comparative analysis with a clinically approved PEGylated LNP formulation (ALC-LNP).

Main Results:

• Optimized pDLS-LNPs demonstrated high mRNA encapsulation and transfection efficiency, achieving colloidal stability.
• pDLS-LNPs showed superior mRNA delivery and elicited robust immune responses compared to ALC-LNPs, without systemic toxicity.
• Repeated administration of pDLS-LNPs resulted in minimal anti-pDLS IgM production, unlike PEG-based LNPs. pDLS-LNPs exhibited stability for over 6 months under frozen storage.

Conclusions:

• Polypeptide-based pDLS lipids are effective, immunologically inert alternatives to PEG lipids for LNP development.
• pDLS-LNPs offer a safer and potentially more effective platform for mRNA delivery, especially for repeated dosing applications.
• The findings support the advancement of pDLS-LNPs for clinical translation in mRNA-based therapeutics.