One of the key challenges for nucleic acid therapeutics is their delivery into cells. The embedding of nucleic acids in liposomal nanoparticles is often chosen for this purpose - a proven approach, which, however, still leaves open wishes with regard to uptake efficiency and cell/tissue specificity. WP4 applies defined test systems in which molecular libraries of carrier sequences or chemical modifications are iteratively investigated and developed for different applications (siRNA, mRNA, different organs and application routes).

While mRNA vaccines were important in the containment of the COVID-19 pandemic, no antivirals with sufficient efficacy are available against SARS-CoV2. The development of synthetic small interfering RNAs (siRNAs) against virally encoded RNAs has shown initial success, but currently no clinically approved siRNAs with antiviral efficacy are available. WP3 therefore aims to develop chemically modified siRNA conjugates and siRNA formulations with enhanced target specificity. We expect that the results of this WP will result in new approaches for siRNA-based therapy of other viral infections.

The widespread use of classical antibiotics carries the risk of multi-resistance and also leads to unwanted side effects such as damage to the natural bacterial flora. In this subproject, highly selective RNA antibiotics are being developed as a novel approach for the targeted control of pathogenic bacteria. Antisense oligonucleotides are coupled to peptides that bind to specific surface structures of the bacteria, thus enabling the oligonucleotide to be introduced.

WP7 focuses on the observation that macrophages may have a significant role in the development of certain tumors, thus linking them to inflammatory processes. There is increasing evidence that long non-coding RNAs (lncRNAs) control essential functions of macrophages and thus have therapeutic potential. Building on a CRISPR-Cas-based screening of thousands of lncRNAs established by AG Rad, suitable targets will be identified and eventually antisense oligonucleotides against these lncRNAs will be developed.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Currently, there is no therapy that can interfere with the underlying inflammatory processes of COPD. Preliminary work on WP6 showed that the alveolar macrophage and its non-coding RNAs (ncRNAs) have a central role in the development of COPD. The aim of this WP is to develop antisense oligonucleotides against ncRNAs that, by coupling to a ligand, achieve enhanced uptake in alveolar macrophages and thus locally increased drug levels.