Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in infants, young children, and elderly people worldwide. Developing a safe and broadly effective vaccine remains a critical and unmet public health need. This study comparatively evaluated the immunogenicity and protective efficacy of respiratory syncytial virus (RSV) mRNA vaccines expressing a modified G protein extracellular domain (G), delivered via either lipid nanoparticle (LNP) or lipid-polymer hybrid (LPP) platforms. Both RSV G-mRNA elicited robust humoral and cellular immunity in mice. Although the humoral immunity in both groups showed a Th2 bias, the advantage of the LNP platform lies in its ability to simultaneously trigger potent humoral and Th1-type cellular immunity. Comparing the two groups, The LNP group elicited a stronger Th1-biased cellular response, manifested by high expression of cytokines such as IL-2 and TNF-α in CD4T cells, and the production of higher neutralizing antibody titers against A/B subtypes of RSV strains than the LPP group,which elicited slightly higher Th2 bias IgG antibody titers. Viral challenge confirmed that both groups provided effective cross-protection against RSV A2 and B9320, significantly reducing lung viral load and histopathology, with comparable protective efficacy.These findings demonstrate that both platforms enabled robust delivery of the RSV G-mRNA vaccine and generated cross-protective immunity, albeit with divergent response characteristics. These results inform the selection of RSV vaccine delivery platforms aimed at distinct immune correlates of protection. ecto ecto + ecto
