Muscle contribution in lipid nanoparticle mediated mRNA vaccine delivery and efficacy.

The remarkable success of mRNA-lipid nanoparticles (LNP) vaccines during the SARS-CoV-2 pandemic have highlighted the critical role of this cutting-edge technology as a cornerstone for contemporary vaccine innovation. Efforts to enhance mRNA-LNP vaccine efficacy have driven specific interest in optimizing nanoparticle design to improve immune cell transfection. Nevertheless, the precise mechanisms driving immune responses, including cell identity and their activation states within immune and local tissues, remain unclear and system-dependent. Muscle tissue is an ideal site for mRNA vaccine administration due to its ribosome abundance, ensuring efficient translation of the delivered mRNA into the encoded protein. Additionally, the localized nature of muscle injections ensures controlled biodistribution and minimizes systemic side effects, making it a safe and effective route for generating robust immune responses. In line with these observations, we developed a lipid-polymer hybrid nanosystem that effectively complexes mRNA, demonstrating high efficiency in transfecting muscle cells and tissue. Importantly, this delivery resulted in a robust adaptive immune response, characterized by both potent humoral and cellular immunity, highlighting the effectiveness of this nanosystem for mRNA-based vaccination. Overall, these findings highlight the need to consider the role of muscle cells as potential antigen-producing reservoirs in immune modulation when designing mRNA vaccines.