DNA Vectors

The DNA Vector Lab at DKFZ develops next-generation non-viral DNA vector technologies for cell engineering and gene therapy. Our work focuses on safe, scalable, and durable gene delivery with persistent episomal expression in therapeutically relevant cells, with applications across both ex vivo and in vivo gene therapy.

We aim to improve how cells are genetically modified for research and therapeutic use. By combining molecular innovation with translational application, we develop vector platforms that support advanced workflows in cell and gene therapy, with a particular emphasis on immunotherapy and next-generation gene therapy approaches.

Our research is centered on the design and optimization of DNA vectors for stable transgene expression. A major goal is to enable efficient, non-integrating gene delivery while minimizing silencing, loss of expression, and other limitations of conventional vector systems.

We work across T cells, NK cells, stem cells, and other therapeutically relevant cell types. We are especially interested in applications in cell and gene therapy, including engineered T-cell and NK-cell products and next-generation immunotherapies.

The lab develops non-viral DNA vector platforms based on episomal maintenance and sustained expression. These systems are designed to provide robust gene expression without genomic integration, supporting safer and more flexible cell modification.

Our technology platform is modular and adaptable for translational applications. We continuously refine the composition of our vectors to improve their performance, including enhanced nuclear uptake, establishment efficiency, and long-term episomal maintenance. In parallel, we are engineering next-generation, highly sophisticated vectors designed to express complex multi-gene cassettes, enabling coordinated regulation of multiple transgenes within a single DNA construct. We are also working to make our DNA vectors compatible with lipid nanoparticles (LNPs) and related formulations to enable in vivo cell and gene therapy applications, including adaptation of vector architecture and production processes for efficient and safe delivery.

Our nanoSMAR vectors are a next-generation non-viral DNA vector platform designed for durable gene expression in therapeutic cells. They combine episomal maintenance with high genetic cargo capacity and are intended to support safe, efficient cell engineering without genomic integration.

The platform is being advanced for applications in cancer immunotherapy and cell therapy, including the INVENT4GB trial, where nanoSMAR vectors will be used in humans for the first time in a first-in-human study of TCR-engineered T cells for glioblastoma.

In addition to cell engineering and cancer immunotherapy, we are broadly interested in non-viral gene therapy across a range of indications. One example is our work on inherited retinal diseases such as choroideremia and Usher syndrome, where large or complex therapeutic payloads make flexible DNA vector design particularly valuable.

These retinal gene therapy projects illustrate the versatility of our platform and its potential to support durable gene expression in settings where safety, cargo capacity, and vector design flexibility are critical, while remaining complementary to our core focus on cell and gene therapy for cancer and other diseases.

We collaborate with academic and industry partners to accelerate the development and translation of DNA vector technologies. These partnerships help us refine vector design, expand application areas, and move promising concepts toward real-world use in cell and gene therapy.

We value interdisciplinary exchange and close interaction with partners in research and biotechnology.

Our team is interdisciplinary and international, bringing together expertise in vector design, cell engineering, translational research, and laboratory development. The group is led by Dr. Richard Harbottle, Head of Division DNA Vectors at DKFZ.

Team members include Leonie Binder, Luisa Burger, Patrick Derigs, Fabian Girke, Annabel Grewenig, Yannick Koch, Hankun Li, Silvia Rizzato, Beeke Tappe, Sophie Williams, and Burak Özbürün. Together, we work across discovery research, technical development, and translational project support.

1. Schifflers, C., Zottnick, S., Förster, J.D., Kruse, S., Yang, R., Wiethoff, H., Bozza, M., Hoppe-Seyler, K., Heikenwälder, M. and Harbottle, R.P. (2023) Development of an Orthotopic HPV16-Dependent Base of Tongue Tumor Model in MHC-Humanized Mice. Pathogens, 12, 188.

2. Roig-Merino, A., Urban, M., Bozza, M., Peterson, J.D., Bullen, L., Büchler-Schäff, M., Stäble, S., van der Hoeven, F., Müller-Decker, K. and McKay, T.R. (2022) An episomal DNA vector platform for the persistent genetic modification of pluripotent stem cells and their differentiated progeny. Stem Cell Reports, 17, 143-158.

3. Hongu, T., Pein, M., Insua-Rodriguez, J., Gutjahr, E., Mattavelli, G., Meier, J., Decker, K., Descot, A., Bozza, M., Harbottle, R., et al (2022) Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs. Nature Cancer, 3, 486-504.

4. Chan, T., Grisch-Chan, H.M., Schmierer, P., Subotic, U., Rimann, N., Scherer, T., Hetzel, U., Bozza, M., Harbottle, R. and Williams, J.A. (2022) Delivery of non-viral naked DNA vectors to liver in small weaned pigs by hydrodynamic retrograde intrabiliary injection. Molecular Therapy-Methods & Clinical Development, 24, 268-279.

5. Thornton, C.D., Fielding, S., Karbowniczek, K., Roig-Merino, A., Burrows, A.E., FitzPatrick, L.M., Sharaireh, A., Tite, J.P., Mole, S.E. and Harbottle, R.P. (2021) Safe and stable generation of induced pluripotent stem cells using doggybone DNA vectors. Molecular Therapy-Methods & Clinical Development, 23, 348-358.

6. Bozza, M., De Roia, A., Correia, M.P., Berger, A., Tuch, A., Schmidt, A., Zörnig, I., Jäger, D., Schmidt, P. and Harbottle, R.P. (2021) A nonviral, nonintegrating DNA nanovector platform for the safe, rapid, and persistent manufacture of recombinant T cells. Science advances, 7, eabf1333.

7. Yang, T., Heydarian, M., Kozjak-Pavlovic, V., Urban, M., Harbottle, R.P. and Rudel, T. (2020) Folliculin Controls the Intracellular Survival and Trans-Epithelial Passage of Neisseria gonorrhoeae. Frontiers in Cellular and Infection Microbiology, 10, 422.

8. Ali, D., Zepp, M., Bozza, M., Nikolova, M., Harbottle, R. and Berger, M.R. (2020) Ly6-neurotoxin1 knockout in PDAC cells inhibits their growth in vitro and in vivo. Cancer Research, 80, 4717-4717.

9. Viarisio, D., Müller-Decker, K., Accardi, R., Robitaille, A., Dürst, M., Beer, K., Jansen, L., Flechtenmacher, C., Bozza, M. and Harbottle, R. (2018) Beta HPV38 oncoproteins act with a hit-and-run mechanism in ultraviolet radiation-induced skin carcinogenesis in mice. PLoS pathogens, 14, e1006783.

10. Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J.K., Green, E. and Deumelandt, K. (2018) Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nature medicine, 24, 1192-1203.