Employing messenger RNA (mRNA) for protein production in the liver or for vaccine purposes is a promising therapeutic approach. However, unlocking mRNA's full therapeutic potential requires systemic delivery platform technology with controllable biodistribution features. Apolipoprotein nanoparticles (aNP) containing monovalent ionizable cationic lipids have been shown to functionally deliver mRNA to myeloid progenitor cells in the bone marrow after intravenous administration. Here, the development of polyvalent ionizable cationic dendrimers is reported for incorporation in aNPs to enable efficient mRNA complexation and functional delivery. A library of dendrimers is first rationally designed with diverse hydrophobic core units, a number of branching units, and functionalized terminal units. Upon incorporation, eleven distinct dendrimer-based aNP-mRNA formulations are screened and characterized in vitro for their properties. Based on the screening outcome, four formulations are selected and evaluated their ability to induce functional gene expression in vivo. The results indicate that the lead polyvalent dendrimer-based aNP formulation outperformed formulations containing a clinically approved ionizable cationic lipid regarding gene expression in hematopoietic stem and progenitor cells in the bone marrow after intravenous administration.
Trines et al. (Fri,) studied this question.