Toward a Complete\nElucidation of the Primary Structure–Activity\nin Pentaerythritol-Based One-Component Ionizable Amphiphilic Janus\nDendrimers for In Vivo Delivery of Luc-mRNA

Four-component lipid nanoparticles (LNPs) and viral vectors\nare\nkey for mRNA vaccine and therapeutics delivery. LNPs contain ionizable\nlipids, phospholipids, cholesterol, and polyethylene glycol (PEG)-conjugated\nlipids and deliver mRNA for COVID-19 vaccines to liver when injected\nintravenously or intramuscularly. In 2021, we elaborated one-component\nionizable amphiphilic Janus dendrimers (IAJDs) accessing targeted\ndelivery of mRNA. Simplified synthesis and assembly processes allow\nfor rapid IAJD screening for discovery. The role of the primary structure\nof IAJDs in activity indicated, with preliminary investigations, that\nionizable amine (IA), sequence, and architecture of hydrophilic and\nhydrophobic domains are important for in vivo targeted delivery. Here,\nwe study the role of the interconnecting linker length between the\nIA and the hydrophobic domain of pentaerythritol-based IAJDs. The\nlinker length determines, through inductive effects, the position\nof the IA and the p<i>K</i><sub>a</sub> of the IAJDs and\nthrough flexibility, the stability of the DNPs, highlighting their\nextraordinarily important role in effective targeted delivery.