Abstract
mRNA is a promising therapeutic nucleic acid, although effective delivery systems are required for its broad application. Polyion complex (PIC) micelles loading mRNA via polyion complexation with block catiomers are emerging as promising carriers for mRNA delivery, but the PIC stability has been limited so far. Controlling the binding of polycations to mRNA could affect the micelle stability. Nevertheless, the impact of binding affinity between polycations and mRNA on the function of mRNA-loaded PIC micelles (mRNA/m) remains unknown. Herein, we review our recent orthogonal approaches controlling the stiffness and the valency of polycations to improve the performance of mRNA/m toward enhancing stability and delivery efficiency. Thus, block catiomers with contrasting flexibility were developed to prepare mRNA/m. The flexible catiomer stabilized mRNA/m against enzymatic attack and polyanion exchange compared to the rigid catiomer, promoting protein translation in vitro and in vivo, and prolonged mRNA bioavailability in blood after systemic injection. Based on these observations, we also developed flexible catiomers with different valencies. The guanidinated catiomer stabilized mRNA/m compared to the aminated catiomers, facilitating intracellular delivery and eventual gene expression. Our findings indicate the importance of controlling the polymer binding to mRNA for developing flexible polycation-based systems directed to in vivo applications.
Highlights
Messenger RNA is a promising therapeutic oligonucleotide though its broad application as a therapeutic agent is confronted by several challenges, including its rapid degradation by nucleases and limited cellular uptake [1]
Polyion complex (PIC) micelles can be disassembled by biomolecules such as glycosaminoglycan existing as polyanions in kidney basement membrane [5]
We investigated the effect of polymer flexibility on the stability and the performance of Messenger RNA (mRNA)-loaded PIC micelles (mRNA/m) by synthesizing poly(ethylene glycol) (PEG)-poly(glycidyl butyl amine) (PEG-PGBA) with flexible polyether backbone and PEG-poly(L-Lysine) (PEG-PLL) with rigid polyamide backbone, and assembling mRNA/m to correlate with their performance in vitro and in vivo (Scheme 1) [9]
Summary
Messenger RNA (mRNA) is a promising therapeutic oligonucleotide though its broad application as a therapeutic agent is confronted by several challenges, including its rapid degradation by nucleases and limited cellular uptake [1]. The development of carrier systems capable of protecting mRNA is essential for mRNA-based therapies. Polyion complex (PIC) micelles comprising block copolymers with poly(ethylene glycol) (PEG) and polycation segments are promising nanocarriers for mRNA delivery [2]. These micelles can load mRNA in the core via electrostatic interaction with the polycation blocks, protecting it from the harsh biological environments by the PEG corona [3,4]. Several systems including the introduction of hydrophobic groups into the core of mRNA/m [6] and the crosslinking
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