Development of Thermostable and Immunogenic Block Copolymer Nanoparticles (BNPs) for mRNA Delivery

Combining an amphiphilic block copolymer polybutadiene-<i>b</i>-poly(ethylene glycol) (PBD-<i>b</i>-PEO), an ionizable lipid, a helper lipid, and cholesterol produces thermostable BNPs. Luciferase mRNA-BNPs can be stored for over 1 year at 4 °C with no evidence of degradation to the mRNA or nanocarrier. In vivo, mRNA-BNPs exhibit a greater affinity for secondary lymphoid organs than mRNA-lipid nanoparticles (LNPs) and are efficiently taken up by macrophages and dendritic cells. Freshly fabricated ovalbumin (OVA) mRNA-BNPs elicit robust OVA-specific IgG and functional memory CD8⁺ T cells that persist for at least 5 months. Immunogenicity remains intact after 24 weeks of storage at 4 °C. Anti-PEG antibodies are not boosted by the repeated administration of mRNA-BNPs, unlike mRNA-LNPs. Syrian hamsters vaccinated with SARS-CoV-2 spike mRNA-BNPs are protected against weight loss associated with infection and potently suppress pulmonary viral loads. Protective efficacy is comparable to that conferred by a Comirnaty biosimilar. Cumulatively, mRNA-BNPs are thermostable, immunogenic and possess the potential for clinical application.