期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 43, 页码 17975-17982出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c09585
关键词
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资金
- National Science Foundation [DMR-2104554, DMR-1720530]
- P. Roy Vagelos Chair at the University of Pennsylvania
- Alexander von Humboldt Foundation
- NSF Major Research Instrumentation Program [NSF CHE1827457]
- Vagelos Institute for Energy Science and Technology
Efficient delivery of nucleic acids is crucial in genetic nanomedicine, and lipid nanoparticles as well as Janus dendrimers have shown great success in delivering mRNA for Covid-19 vaccines. By modifying the structure, targeted delivery of mRNA using Janus dendrimers can be switched from lung to liver and spleen, expanding the utility of dendrimersome nanoparticles from therapeutics to vaccines.
Targeted and efficient delivery of nucleic acids with viral and synthetic vectors is the key step of genetic nanomedicine. The four-component lipid nanoparticle synthetic delivery systems consisting of ionizable lipids, phospholipids, cholesterol, and a PEG-conjugated lipid, assembled by microfluidic or T-tube technology, have been extraordinarily successful for delivery of mRNA to provide Covid-19 vaccines. Recently, we reported a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) synthetic delivery system for mRNA relying on amphiphilic Janus dendrimers and glycodendrimers developed in our laboratory. Amphiphilic Janus dendrimers consist of functional hydrophilic dendrons conjugated to hydrophobic dendrons. Co-assembly of IAJDs with mRNA into dendrimersome nanoparticles (DNPs) occurs by simple injection in acetate buffer, rather than by microfluidic devices, and provides a very efficient system for delivery of mRNA to lung. Here we report the replacement of most of the hydrophilic fragment of the dendron from IAJDs, maintaining only its ionizable amine, while changing its interconnecting group to the hydrophobic dendron from amide to ester. The resulting IAJDs demonstrated that protonated ionizable amines play dual roles of hydrophilic fragment and binding ligand for mRNA, changing delivery from lung to spleen and/or liver. Replacing the interconnecting ester with the amide switched the delivery back to lung. Delivery predominantly to liver is favored by pairs of odd and even alkyl groups in the hydrophobic dendron. This simple structural change transformed the targeted delivery of mRNA mediated with IAJDs, from lung to liver and spleen, and expands the utility of DNPs from therapeutics to vaccines.
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