posted on 2021-10-21, 20:18authored byDapeng Zhang, Elena N. Atochina-Vasserman, Devendra S. Maurya, Matthew Liu, Qi Xiao, Juncheng Lu, George Lauri, Nathan Ona, Erin K. Reagan, Houping Ni, Drew Weissman, Virgil Percec
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.