We are comparing and contrasting tumor specificity and transduction efficiency of novel polyplexes and engineered MSCs in more advanced tumor models, including a transgenic orthotopic pancreatic cancer mouse model and multifocal liver cancer and hepatic colon cancer metastasis mouse models. In addition to EGFR-targeted nanoparticles, we are evaluating further tumor-specific ligands for active tumor targeting of linear polyethylenimine (LPEI)-based polymers and novel sequence-defined oligo(ethanamino)amides as biodegradable carriers. Further, we are exploring the combination of polyplex- or MSC-mediated NIS gene delivery with external beam radiation therapy (EBRT), which offers several advantages.