Ionizable amino lipid interactions with POPC: implications for lipid nanoparticle function

Abstract

The distribution of ionizable amino lipids (KC2) is critical in structure of lipid nanoparticles, siRNA entrapment and endosomal release. Neutral KC2 segregates from phospholipids (POPC) and forms an oily core in the bilayer interior.

DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA

“…The headgroup of the amine lipid ''prefers'' to be located in the region of the phospholipid headgroups, but in the membrane with DOPC a small amount was detected even in the center of the lipid bilayer. Such a location of DLin-MC3-DMA is slightly similar to the one which was observed by Ramenzapour et al 24 in simulations of DLin-KC2-DMA in a membrane containing POPC and cholesterol at a neutral pH.…”

“…A small number of theoretical studies have been done with DLin-KC2-DMA, but no computational study has been performed with DLin-MC3-DMA, probably, due to the absence of numerical models. Ramenzapour et al 24 combined MD simulations with cryo-TEM and SAXS for investigating membranes, formed by POPC, cholesterol and the ionizable lipid, at acidic and neutral pH. According to their study, whole molecules of DLin-KC2-DMA preferred to reside in the center of the lipid bilayer at pH 7.4 while at higher pH the ionizable lipids were positioned with headgroups towards the membrane surface and their tails were spread between the tails of POPC.…”

“…According to their study, whole molecules of DLin-KC2-DMA preferred to reside in the center of the lipid bilayer at pH 7.4 while at higher pH the ionizable lipids were positioned with headgroups towards the membrane surface and their tails were spread between the tails of POPC. 24 Leung et al 25 went towards the lower resolution in computer simulations by carrying out coarse-grained (CG) simulations of whole LNPs and combining them with 31 P NMR and cryo-TEM techniques. Their vehicles contained DLin-KC2-DMA, siRNA duplexes, DSPC, cholesterol and pegylated lipid.…”

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

“…This technique has shown efficient mRNA delivery for tumor antigen loading of DCs [81]; even in some studies, mRNA electroporation has been more efficient than DNA electroporation, with faster and more homogeneous protein expression in vivo [82]. The direct injection of mRNA into the target cell by the use of microneedles (namely, microinjection) [83,84], and gene gun, in which naked mRNA is pneumatically shot into the target cell, have also been used for mRNA transfection [85][86][87][88]. In in vivo applications, intravenously administered naked mRNA is rapidly degraded by ribonucleases and the innate immune system can be activated.…”

“…These new lipids are neutral at physiological pH but positively charged inside the endosome, when pH values are below its pKa. The electrostatic interactions between naturally occurring anionic lipids in endosomal membranes and the ionizable cationic lipids have been proposed as the underlying mechanism of nucleic acid release [88]. These interactions are able to promote membrane lytic nonbilayer structures, such as the hexagonal H II phase, culminating in the intracellular mRNA delivery [98].…”