HYBRID EVENT: You can participate in person at Rome, Italy or Virtually from your home or work.
Speaker at Drug Delivery Events - Ernst Wagner
Ludwig-Maximilians-Universitat Munich, Germany
Title : Chameleon nanocarriers for dynamic delivery of RNA Medicines


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 xenopeptide 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 the spleen, tumor, lung, and liver upon intravenous administration of 1 µg luciferase mRNA.

Audience Take Away Notes:

  • Explains how bioinspired chemical evolution can be applied to optimize RNA carriers
  • Chemical evolution is based on precise sequences of defined building blocks
  • Sequence-defined xenopeptides are assembled by solid-phase synthesis using artificial amino acids
  • Intracellular delivery transporters must be dynamic to be efficient on nanoparticle basis


Dr. Wagner is full professor of Pharmaceutical Biotechnology at LMU since 2001 and member of the Munich Center for Nanoscience. He coordinates ‘Biomedical Nanotechnologies’ of the Excellence Cluster NIM. After a PhD from TU Vienna and postdoc at ETH Zürich, he was Group Leader at the IMP Vienna (1987-1995) and Director for Cancer Vaccines at BoehringerIngelheim Austria (1992-2001). Dr. Wagner has authored >403 publications (h-index 72). He is Board member of the German Society for Gene Therapy, Committee member of ASGCT, and BSA member of CRS. He is Editor of Pharmaceutical Research and Editor-in-Chief of The Journal of Gene Medicine.