Accelerated Ten-Gram-Scale Synthesis of One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus...

One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimers (IAJDs) were discovered in our laboratories in 2021 to represent a new class of synthetic vectors for the targeted delivery of messenger RNA (mRNA). They coassemble with mRNA by simple injection of their ethanol solution into a pH 4 acetate buffer containing the nucleic acid into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions. DNPs are competitive with 4-component lipid nanoparticles (LNPs), which are used in commercial COVID-19 vaccines, except that IAJDs are prepared in fewer reaction steps than each individual component of the LNPs. This simple methodology for the synthesis of IAJDs and their coassembly with mRNA into DNPs, together with the precise placement of their individual components and indefinite stability at room temperature in air, make them attractive candidates for the development of nanomedicine-based targeted mRNA delivery. Access to the large-scale synthesis of IAJDs without the need for sophisticated technologies, instrumentation, and synthetic skills is expected to open numerous new opportunities worldwide in nanomedicine. The goal of this publication is to report an accelerated ten-gram-scale synthesis of IAJD97 from inexpensive food additives obtained from renewable plant phenolic acid starting materials by methodologies accessible to any laboratory. This accelerated synthesis can be accomplished in 4 days. We expect that the work reported here will impact the field of nanomedicine in both developed and less developed countries.