Engineering LNPs with polysarcosine lipids for mRNA delivery

Area of Science:

• Biotechnology
• Nanomedicine
• Vaccine Development

Background:

• Lipid nanoparticles (LNPs) are crucial for mRNA vaccine delivery, notably for SARS-CoV-2 vaccines.
• Current LNP formulations utilize polyethylene glycol (PEG) lipids, which can elicit anti-PEG antibodies.
• Anti-PEG antibodies may lead to adverse reactions and reduced therapeutic effectiveness.

Purpose of the Study:

• To investigate polysarcosine (pSar) lipids as potential replacements for PEG lipids in LNP formulations.
• To assess if pSar lipids can retain the functional properties of PEG lipids in established LNP systems (ALC-0315 and SM-102).
• To evaluate the safety and efficacy of pSar-based LNPs for mRNA delivery.

Main Methods:

• Synthesized and characterized LNP formulations with varying ratios of pSar lipids replacing PEG lipids.
• Assessed mRNA encapsulation and in vitro release kinetics.
• Evaluated in vivo mRNA delivery efficiency and biodistribution in preclinical models.
• Monitored immune responses and potential adverse effects related to PEG and pSar components.

Main Results:

• Complete replacement of PEG lipids with pSar lipids in ALC-0315 and SM-102 LNP systems was achieved.
• pSar-based LNPs demonstrated comparable or enhanced mRNA delivery efficiency compared to PEG-based LNPs.
• In vivo safety profiles of pSar-containing LNPs were found to be similar to those of traditional PEG-containing LNPs.
• No significant increase in adverse reactions was observed with pSar lipid incorporation.

Conclusions:

• Polysarcosine (pSar) lipids are viable alternatives to polyethylene glycol (PEG) lipids for mRNA delivery via lipid nanoparticles (LNPs).
• pSar-based LNPs maintain or improve mRNA delivery efficacy and exhibit favorable safety profiles, mitigating concerns associated with anti-PEG antibodies.
• These findings support the development of next-generation LNP formulations for mRNA therapeutics and vaccines with potentially reduced immunogenicity.