A Potent Branched-Tail Lipid Nanoparticle Enables Multiplexed mRNA Delivery and Gene Editing In Vivo

Abstract

The clinical translation of messengerRNA (mRNA) drugs has been slowed by a shortage of delivery vehicles that potently and safely shuttle mRNA into target cells. Here, we describe the properties of a particularly potent branched-tail lipid nanoparticle that delivers mRNA to >80% of

Lipid nanoparticle technology for therapeutic gene regulation in the liver

“…Higher LNP doses corresponding to 1 mg/kg mRNA shifted expression slightly towards hepatocytes while keeping the same pattern. Transfection of all major liver cell types with equal potency was recently demonstrated for LNP-mRNA systems (composed of branched-tail 306O i10 ) at a dose of mg RNA/kg by Hajj et al [51].…”

Nanomaterial Delivery Systems for mRNA Vaccines

“…Notably, all of the above charge-mediated targeting studies have been done using IV administration and the routes typically used for vaccination, such as the intramuscular or intradermal routes, have not been examined. Most studies that analyze expression after intramuscular injection do, however, detect the systemic trafficking of mRNA LNPs, which are rapidly and strongly expressed in the liver, at the same time as they are expressed in muscle and draining lymph nodes [ 97 , 156 , 157 ]. These particular LNPs therefore seem to enter the vasculature and are subsequently expressed in liver hepatocytes due to passive ApoE-mediated targeting, which is not surprising since they were designed for hepatocyte targeting.…”

Biomedically Relevant Applications of Bolaamphiphiles and Bolaamphiphile-Containing Materials

“…The Whitehead group made further progress in RNA delivery using branched tail lipid nanoparticles having an inverse BA-type architecture (Hajj et al, 2020 ). This particular type of lipid was shown to co-deliver, in vivo , three unique mRNAs.…”

“…The polar head groups can be uniform or varied (i.e., asymmetric BAs) but the triblock segmented structure is required. An increasing number of “inverted bolaamphiphiles” have appeared in the literature featuring a polar central spacer flanked by nonpolar head groups (Hajj et al, 2020 ; Wei et al, 2020 ; Xiong et al, 2020 ). Given the possible confusion in regard to the terminology of these types of molecules, it seems important to define a BA based on its segmented amphiphilic structure (A-B-A), not on the ordering of the hydrophilic and hydrophobic segments.…”