Vitamin E-Engineered Anti-Inflammatory Lipid Nanoparticles for Safer mRNA Delivery

Abstract Great strides have been achieved in lipid nanoparticle (LNP)-mediated mRNA delivery. However, traditional LNPs can induce undesirable side effects such as inflammatory reactions. Oxidative stress damage arising from ionizable lipids within LNPs is regarded as a major underlying cause of these adverse effects. Herein, we propose incorporating endogenous vitamin E (VE) into the tail moiety of commercial ionizable lipids to improve biosafety. Proof-of-concept investigations using SM-102-derived W3 confirm that this endogenous antioxidant modification substantially mitigates the inflammatory toxicity of mRNA-loaded LNPs. Following intravenous administration, W3 LNPs markedly decrease the levels of multiple pro-inflammatory cytokines, demonstrating an improved safety profile compared to SM-102 LNPs. Further analysis reveals that W3 LNPs significantly reduce intracellular reactive oxygen species (ROS) levels, alleviate oxidative stress damage, thereby inhibiting the activation of key inflammatory pathways such as NF-κB. Of note, the optimized formulation, sW3 LNPs enable efficient mRNA delivery to the spleen, with stronger antitumor efficacy and higher safety than SM-102 LNPs. In summary, W3 lipid confers minimal inflammatory adverse effects while preserving excellent delivery capability, which indicates that the VE-engineered LNPs possess great potential to serve as powerful and multifunctional platforms for next-generation mRNA therapeutics.