Effective mRNA protection by poly(l-ornithine) synergizes with endosomal escape functionality of a charge-conversion polymer toward maximizing mRNA introduction efficiency

April 4, 2022 (Kawasaki, Japan) - Innovation Center of NanoMedicine (Director General: Prof. Kazunori Kataoka) has announced that Prof. Satoshi Uchida et al. presented their research results about optimization of nanocarriers for mRNA delivery on Macromolecular Rapid Communications issued on March 14, 2022. For efficient delivery of mRNA, delivery carriers need two major functions: protecting mRNA from nucleases and translocating mRNA from endolysosomes to the cytoplasm. Herein, these two complementary functionalities are integrated into a single polyplex by fine-tuning the catiomer chemical structure and incorporating the endosomal escape modality. They successfully solved the two issues of mRNA delivery, enzymatic mRNA degradation and limited endosomal escape, by developing a ternal polyplex (TP) formulated with poly(L-ornithine) (PLO) and CCP, which is negatively charged at extracellular pH but turns positive at endosomal acidic pH to disrupt the endosomal membrane. Compared to the parent PLO/mRNA polyplex, CCP facilitated the endosomal escape of the polyplex in cultured cells to improve the protein expression efficiency from mRNA by approximately 80-fold. Collectively, this system synergizes the protective effect of PLO against nucleases and the endosomal escape capability of CCP in mRNA delivery. Remarkably, compared to PLL, PLO improved the mRNA delivery efficiency regardless of the use of charge-conversion Polymer (CCP), despite PLO differing from poly(L-lysine) (PLL). The superior functionalities of PLO can be attributed to improved nuclease tolerability, which might result from the stronger mRNA affinity of PLO than that of PLL. 

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Makoto Shimazaki, Ph.D. / Communications Manager: shimazaki-m@kawasaki-net.ne.jp

Misato Yamamoto / Communications Coordinator: yamamoto-m@kawasaki-net.ne.jp