Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Area of Science:

• Biotechnology
• Vaccinology
• Materials Science

Background:

• Self-amplifying mRNA (SAM) vaccines show promise for infectious diseases due to self-adjuvating and dose-sparing capabilities.
• Current lipid nanoparticle (LNP) delivery systems for mRNA vaccines face challenges in cold storage, manufacturing, and delivery efficiency.
• Degradation of SAM and the requirement for intact delivery to the cytosol are key hurdles in SAM vaccine development.

Purpose of the Study:

• To develop and evaluate biodegradable polymer-based alternatives to LNPs for efficient SAM delivery.
• To investigate the potential of poly(beta-amino ester)s (PBAEs) for intramuscular delivery of SAM vaccines.
• To assess the immunogenicity of SAM delivered via polymer nanoparticles.

Main Methods:

• Synthesis and characterization of over 200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs).
• In vitro and in vivo evaluation of PBAE formulations for SAM delivery, measuring reporter protein expression.
• Intramuscular (IM) delivery of SAM-based rabies virus glycoprotein vaccine in mice using optimized PBAE nanoparticles.

Main Results:

• A novel PBAE formulation demonstrated up to 37-fold higher IM SAM expression compared to naked SAM.
• Polymer nanoparticle delivery of SAM resulted in superior immunogenicity compared to naked SAM.
• Low RNA doses of the SAM vaccine delivered via PBAE nanoparticles induced seroconversion in mice.

Conclusions:

• Biodegradable PBAE nanoparticles are effective delivery vehicles for SAM, overcoming limitations of current LNP technology.
• These nanomaterials show potential for developing next-generation RNA vaccines against infectious diseases.
• The developed PBAE formulations offer improved SAM delivery and vaccine efficacy.