Nucleic acids such as small interfering RNA (siRNA) or plasmid DNA (pDNA) present encouraging new therapeutic options [1]. Programmed nanosystems are emerging which may be very useful for tumor targeted delivery of therapeutic nucleic acids. These nanoparticles (Figure 1) can be pre-programmed to change their structure during drug delivery and make them most effective for overcoming the different delivery barriers [2]. Molecular sensors (e.g. sensitive chemical bonds) are responsible for the programmed changes. Natural viruses are very effective in nucleic acid delivery; we want to program polymer-based nanosystems into “synthetic viruses” [3].

Polymers for nucleic acid packaging include polyethylenimine (PEI) and biocompatible cationic polymers [4]. Tumor targeting principles may combine systemic passive targeting and active receptor targeting. The surface of nucleic acid complexes (polyplexes) can be shielded with polyethylene glycol (PEG), targeting to tumors be enhanced by tumor cell binding ligands such as epidermal growth factor (EGF). Intracellular escape from the endosomal compartment can be enhanced by peptides [5]. Biooptical studies [6] demonstrated uptake of EGFR-targeted polyplexes, involving the actin cytoskeleton followed by a dynamic transport process along microtubules and localization in perinuclear vesicles within 10 minutes.

Targeted polyplexes have been tested in first therapeutic studies. EGFR targeted polyplexes containing poly inosine/cytidine RNA induced rapid cell killing in EGFR overexpressing tumors including glioblastoma. Mice with orthotopical glioblastoma when intratumorally treated with the “synthetic RNA virus” showed complete tumor regression [7].