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Updated: Jun 25, 2025
Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA
Published on: February 1, 2019
Isoprenoid CARTs: In Vitro and In Vivo mRNA Delivery by Charge-Altering Releasable Transporters Functionalized with
Harrison P Rahn1, Jiuzhi Sun1, Zhijian Li1
1Department of Chemistry, Stanford University, Stanford, California 94305, United States.
Abstract:
The delivery of oligonucleotides across biological barriers is a challenge of unsurpassed significance at the interface of materials science and medicine, with emerging clinical utility in prophylactic and therapeutic vaccinations, immunotherapies, genome editing, and cell rejuvenation. Here, we address the role of readily available branched lipids in the design, synthesis, and evaluation of isoprenoid charge-altering releasable transporters (CARTs), a pH-responsive oligomeric nanoparticle delivery system for RNA. Systematic variation of the lipid block reveals an emergent relationship between the lipid block and the neutralization kinetics of the polycationic block. Unexpectedly, iA21A11, a CART with the smallest lipid side chain, isoamyl-, was identified as the lead isoprenoid CART for the in vitro transfection of immortalized lymphoblastic cell lines. When administered intramuscularly in a murine model, iA21A11-mRNA complexes induce higher protein expression levels than our previous lead CART, ONA. Isoprenoid CARTs represent a new delivery platform for RNA vaccines and other polyanion-based therapeutics.
