Development of self-degradable lipid-like material equipped with environment sensing units

An in-vitro transcribed messenger RNA (mRNA) is now becoming one of the most powerful tools for introducing a desired protein to cells and organisms. We previously developed a lipid-like material (COATSOME^® SS-series) for the successful cytoplasmic delivery of the mRNA. COATSOME^® SS-series contain two environment sensing units; tertiary amines for endosomal escape and a disulfide bonding for cytoplasmic collapse [1, 2]. In this study, we further improved the cytoplasmic release of the mRNA from the lipid nanoparticles by modifying the structure of COATSOME^® SS-series.

We have recently discovered that an enrichment of hydrophobic thiols in the particle under reducing environments induces an intra-particle hydrolysis reaction. In this study, we introduced a hydrolysable phenyl ester group to COATSOME^® SS-OP (Fig. 1) as a self-degradation unit.

The self-degradation reaction was confirmed using high performance liquid chromatography, liquid chromatography–mass spectrometry, and nuclear magnetic resonance spectroscopy. Transmission electron cryomicroscopy observation revealed that the mRNA-encapsulating particle has a spherical and homogenous morphology. The COATSOME^® SS-OP showed potent gene expressions in both in-vitro and in-vivo assays.