Chameleon Nanocarriers for Dynamic Delivery of Therapeutic RNA | Ernst Wagner
Summary :
Twenty two RNA therapies reached the medical market by Q1 2023. Targeted intracellular delivery remains the key requirement. For refinements of nanocarriers we focus on a bioinspired, sequence-defined process including (i) artificial amino acids (ii) precise assembly into sequences by solid phase-assisted synthesis (iii) screening for delivery and selection of top candidates. A recent chemical evolution library combined aminoethylene amino acids as polar protonatable units with novel lipo amino fatty acids (LAFs) as hydrophobic protonatable motifs. These novel double pH-responsive nucleic acid carriers utilize intracellular delivery mechanisms of both cationizable lipids and cationic polymers. The endosomal pH-dependent tunable polarity of LAF was successfully implemented by a central tertiary amine, which disrupts the hydrophobic character once protonated, resulting in drastic pH-dependent change in the logarithmic (octanol/ water) distribution logD from around +1 (pH 7.4) to -1 (pH 5.5). This “molecular chameleon character” turned out to be advantageous for mRNA, siRNA or CRISPER/Cas9 sgRNA delivery. The efficiency of best performers was up to several 100-fold higher compared to previous carriers. Transfection activity of mRNA lipoplexes was maintained even in the presence of 90% serum and at extremely low dosage of 3 pg mRNA (~2 nanoparticles/cell), in the range of the viral potency. mRNA lipoplexes showed great in vivo performance in mice with high expression levels in spleen, tumor, lung, and liver upon intravenous administration of 1 μg luciferase mRNA.
About Author :
Ernst Wagner is professor of Pharmaceutical Biotechnology and Center of NanoScience at LMU Munich since 2001. From 1992-2001 he was Director Cancer Vaccines, Boehringer Ingelheim (first polymer-based gene therapy trial in 1994), 1987-1995 group leader at IMP Vienna and Vienna University Biocenter, 1985-1987 postdoc at ETH Zurich, in 1985 PhD in chemistry (TU Vienna). He is Academician of European Academy of Sciences, member of CRS College of Fellows, Board member of German Society for Gene Therapy. He has authored 500 publications, with 50 503 citations, h-index 112 (GS).
