The Unexpected Importance of the Primary Structure of the Hydrophobic Part of One-Component Ionizable Amphiphilic Janus Dendrimers in Targeted mRNA Delivery Activity

作者：Dapeng Zhang, Elena N. Atochina‐Vasserman, Juncheng Lu, Devendra S. Maurya, Qi Xiao, Matthew Liu, Jasper Adamson, Nathan Ona, Erin K. Reagan, Houping Ni, Drew Weissman, Virgil Percec · 发表于：Journal of the American Chemical Society · 年份：2022 · DOI：10.1021/jacs.2c00273 · 被引用次数：107 · 研究领域：RNA Interference and Gene Delivery、Immunotherapy and Immune Responses、Dendrimers and Hyperbranched Polymers

Viral and synthetic vectors for delivery of nucleic acids impacted genetic nanomedicine by aiding the rapid development of the extraordinarily efficient Covid-19 vaccines. Access to targeted delivery of nucleic acids is expected to expand the field of nanomedicine beyond most expectations. Both viral and synthetic vectors have advantages and disadvantages. The major advantage of the synthetic vectors is their unlimited synthetic capability. The four-component lipid nanoparticles (LNPs) are the leading nonviral vector for mRNA used by Pfizer and Moderna in Covid-19 vaccines. Their synthetic capacity inspired us to develop a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA. The first experiments on IAJDs provided, through a rational-library design combined with orthogonal-modular accelerated synthesis and sequence control in their hydrophilic part, some of the most active synthetic vectors for the delivery of mRNA to lung. The second experiments employed a similar strategy, generating, by a less complex hydrophilic structure, a library of IAJDs targeting spleen, liver, and lung. Here, we report preliminary studies designing the hydrophobic region of IAJDs by using dissimilar alkyl lengths and demonstrate the unexpectedly important role of the primary structure of the hydrophobic part of IAJDs by increasing up to 90.2-fold the activity of targeted delivery of mRNA to spleen, lymph nodes, liver, and lung. The pri...