Messenger RNA (
mRNA) has recently come into focus as an emerging therapeutic class with great potential for
protein replacement
therapy,
cancer immunotherapy, regenerative medicine,
vaccines, and gene editing. However, the lack of effective and safe delivery methods impedes the broad application of
mRNA-based
therapeutics. We report a robust approach to develop efficient polymeric delivery carriers for
mRNA. Lead
polyesters were identified by in vitro screening of a 480-member combinatorially modified poly(
trimethylolpropane allyl
ether-co-suberoyl
chloride) library for the delivery of
luciferase encoding
mRNA (Luc
mRNA) to IGROV1 cells. The formulation of
mRNA polyplex nanoparticles (NPs) with
Pluronic F127 decreased the surface charge. Although this improved the stability of
mRNA nanoparticles, the delivery potency decreased with increased
F127 content. Thus, we determined that NP stabilization with 5%
F127 could balance the protective effects and delivery potency. 5%
F127 formulated PE4K-A17-0.33C12
mRNA NPs enabled
luciferase expression predominantly in the lungs after
intravenous injection into mice. The efficient
mRNA delivery specifically to lungs by degradable carriers suggests the potential for the treatment of
pulmonary diseases.