Synergistic targeted (SynTar) lipid nanoparticles enhance the efficacy and specificity of mRNA delivery in lungs

Lipid nanoparticles (LNPs) have shown great potential in mRNA-based therapeutics, but achieving high specificity and efficacy of mRNA-LNPs in extrahepatic tissues remains a challenge. In this study, we introduce a Synergistic Targeted (SynTar) LNP platform featuring antibody-modified tissue-targeted LNPs, significantly improving the mRNA delivery specificity, efficacy, and safety. Through the selective organ targeting (SORT) strategy, we obtain a simplified four-component lung-targeted LNP (4C-DOTAP LNP). Followed by anti-CD31 antibody modification, the developed SynTar LNP dramatically enhances mRNA delivery efficiency, specificity, and safety to the lungs. In a proof-of-concept experiment for lung cancer treatment, SynTar LNP can effectively deliver interleukin-15 superagonist mRNA to realize tumor immunotherapy. Moreover, we explored and verify that the SynTar strategy can also be applied to another kind of lung-tropic LNP driven by a specific lipid structure (A3-N11F LNP). The SynTar A3-N11F LNP exhibits over 4 times higher efficacy and better specificity on lung-selective mRNA delivery, demonstrating the general applicability of SynTar for optimizing both charge- and structure-driven targeted LNPs. In summary, SynTar LNP provides a promising approach to achieving efficient and specific mRNA delivery to target tissues and may broaden the therapeutic window by reducing unexpected toxicities. By combining antibody modification with the inherent targeting properties of lipid nanoparticles (LNPs), this study developed the SynTar platform to comprehensively enhance the targeted delivery of mRNA for disease treatment.