A study published in Nature (DOI: 10.1038/s41467-024-50093-7) presents a novel approach to enhance the targeted delivery of mRNA therapeutics by reformulating lipid nanoparticles (LNPs). The research focuses on achieving simultaneous organ-specific accumulation and translation of mRNA in the lung and liver. The team designed a combinatorial library of degradable-core based ionizable cationic lipids (nAcx-Cm) and optimized LNP compositions to achieve this goal. They found that cholesterol and phospholipid are not essential for LNP functionality, which helps prevent nanoparticle accumulation in the liver. By simplifying the intrinsic components of LNPs, the study achieved efficient mRNA accumulation and translation in both the lung and liver. The findings demonstrate that the removal of cholesterol and phospholipid from LNPs enables true organ-targeted delivery, with the 3-component (3-Comp) LNP strategy showing superior efficacy and targeting properties for lung delivery. The study also highlights the potential of this approach for expanding the application of mRNA therapy to various diseases. The research provides a promising method for developing precise mRNA drugs with minimal side effects, establishing a new standard for targeted delivery technology.A study published in Nature (DOI: 10.1038/s41467-024-50093-7) presents a novel approach to enhance the targeted delivery of mRNA therapeutics by reformulating lipid nanoparticles (LNPs). The research focuses on achieving simultaneous organ-specific accumulation and translation of mRNA in the lung and liver. The team designed a combinatorial library of degradable-core based ionizable cationic lipids (nAcx-Cm) and optimized LNP compositions to achieve this goal. They found that cholesterol and phospholipid are not essential for LNP functionality, which helps prevent nanoparticle accumulation in the liver. By simplifying the intrinsic components of LNPs, the study achieved efficient mRNA accumulation and translation in both the lung and liver. The findings demonstrate that the removal of cholesterol and phospholipid from LNPs enables true organ-targeted delivery, with the 3-component (3-Comp) LNP strategy showing superior efficacy and targeting properties for lung delivery. The study also highlights the potential of this approach for expanding the application of mRNA therapy to various diseases. The research provides a promising method for developing precise mRNA drugs with minimal side effects, establishing a new standard for targeted delivery technology.