Abstract

The inherent immunogenicity of mRNA lipid nanoparticles (LNPs) poses a major challenge to their application in disease treatment. In this study, we developed a series of innovative dexamethasone (DEX) prodrug ionizable lipids (DPILs) to address the need for safe and effective mRNA delivery, leading to the establishment of the Safe and Highly Efficient Lipid-pro-dexamethasone (SHIELD) LNP platform. The lead formulation, DEX-SPM-CP10 SHIELD LNP, not only markedly decreased the levels of multiple proinflammatory cytokines but also achieved mRNA delivery efficiency comparable to that of the FDA-approved SM-102 LNP. Furthermore, the SHIELD platform demonstrated universality, as incorporating specific ratios of DPILs into various LNPs targeting different organs (such as the liver, lungs, spleen, and pancreas) led to notable reductions in inflammatory responses and enhancements in mRNA expression, highlighting its superiority over strategies that incorporate free DEX. Subsequently, we investigated its application in gene editing therapy by codelivering ABEmax mRNA and sgRNA to edit the EGFP reporter gene and endogenous PCSK9 gene, as well as in protein replacement therapy through multiple injections of mRNA-SHIELD LNPs. All of these results demonstrated excellent delivery efficacy with minimal immunogenicity, fully illustrating the therapeutic potential of this platform. Taken together, the SHIELD platform offers safe and efficient mRNA delivery and has the potential to expand the therapeutic applications of mRNA-based therapies.