Design of lipid nanoparticles with potent reactive oxygen species scavenging capacity for efficient mRNA delivery

Lipid nanoparticles (LNPs) have become a clinically established platform for mRNA vaccine delivery, demonstrating significant potential in both infectious disease and cancer immunotherapy. However, excessive intracellular reactive oxygen species (ROS) can impair protein synthesis and compromise vaccine efficacy. To address this limitation, we developed an ionizable lipid incorporating a dopamine-derived moiety (DA lipid) for the formulation of ROS-scavenging LNPs. Comparative studies with oxidized control LNPs (ODA LNPs) revealed that DA LNPs exhibit superior intrinsic antioxidant activity, effectively mitigating intracellular ROS accumulation while supporting higher mRNA-derived protein expression. DA LNPs mediated transfection levels comparable to those achieved with ALC-0315 LNPs (ALC LNPs). In addition, DA LNPs induced stronger antigen-specific immune responses and more potent tumor suppression in a prophylactic mouse melanoma model compared to ODA LNPs. These results support the importance of redox modulation in optimizing mRNA vaccine performance and provide a rational design strategy for advanced nucleic acid delivery systems.