Tuning the Organ-Selectivity of mRNA Expression through Dendrimer-Based Lipid Nanoparticles

Lipid nanoparticles (LNPs) are effective and clinically validated nanocarriers for nucleic acids; however, achieving organ-selective delivery remains challenging as systemically administered LNPs predominantly accumulate in the liver and preferentially target liver hepatocytes. Efficient delivery of nucleic acids beyond the liver is essential for expanding the clinical applications of LNP therapeutics as systemic therapies. To address this challenge, we constructed a library of 162 dendrimer-based ionizable lipids and formulated them with mRNA to create dendrimer-based lipid nanoparticles (dLNPs). The structural-tuning flexibility and molecular uniformity of dendrimers have allowed us to explore how their structural properties influence mRNA-dLNP performance. We identified four spleen-selective and five liver-selective formulations with transfection efficiencies comparable to FDA-approved LNP formulations. Additionally, we discovered a potential correlation between dendrimer-lipid structural properties, such as lipid tails and internal amines, and dLNP physicochemical properties, including apparent pKa and surface lipophilicity, in determining organ selectivity of mRNA expression. Our work aims to guide the rational design of LNPs for systemic extrahepatic targeting, potentially revolutionizing RNA-LNP therapeutic development by enabling organ-selective delivery of therapeutic RNAs in clinical settings.