Circular mRNA Vaccine against SARS-COV-2 Variants Enabled by Degradable Lipid Nanoparticles

The emergence of mRNA vaccines offers great promise and a potent platform in combating various diseases, notably COVID-19. Nevertheless, challenges such as inherent instability and potential side effects of current delivery systems underscore the critical need for the advancement of stable, safe, and efficacious mRNA vaccines. In this study, a robust mRNA vaccine (cmRNA-1130) eliciting potent immune activation has been developed from a biodegradable lipid with eight ester bonds in the branched tail (AX4) and synthetic circular mRNA (cmRNA) encoding the trimeric Delta receptor binding domain of the SARS-CoV-2 spike protein. Notably, the cmRNA-1130 vaccine exhibits outstanding stability, remaining effective after six months of storage at 4 °C and multiple freeze–thaw cycles. In comparison with the commercial MC3 lipid, the nanoparticles formed from the degradable AX4 lipid revealed a much faster metabolic rate from the liver and spleen, affording negligible impairment to the hepatorenal function. Following intramuscular administration, cmRNA-1130 generates robust and sustained neutralizing antibodies and induces the activation of Delta RBD-specific CD4+ and CD8+ T effector memory cells (TEM) and Th1-biased T cells in mice. Featured with potent immune activation, high stability, and decent safety, vaccines formed from cmRNA and AX4 hold a huge clinical potential for the prophylaxis and treatment of different diseases.