Shahrzad Bastani

Master student

Acid Stable Lipids for Oral Drug Delivery of mRNA

Supervisors: Prof. Dr. Dagmar Fischer, Prof. Dr.-Ing. Aldo R. Boccaccini

mRNA lipid nanoparticles have been clinically approved for vaccination and have proven their outstanding success during the COVID-19 pandemic. However, their instability during storage and their sensitivity to acidic conditions, enzymatic degradation, and temperature variations remain significant challenges that restrict their application for oral delivery.
This research investigates the development of novel lipid-based nanocarriers designed to overcome the physiological barriers associated with oral mRNA delivery. The study focuses on the formation and characterization of modified archaeosomes incorporating archaeal tetraether lipids. These acid-stable lipids exhibit exceptional resistance to low pH and enzymatic degradation, making them a promising alternative to conventional phospholipids for oral delivery applications.

To enhance delivery efficiency, the lipids head groups are further modified to electrostatically promote efficient mRNA binding and pH-responsive endosomal escape, while PEGylation is employed to improve particle stability and biocompatibility. The resulting nanocarriers are systematically evaluated with respect to their physicochemical properties, mRNA binding efficiency, in vitro stability, and biological performance under simulated gastrointestinal conditions to set up structure-activity relationships for further targeted development of archaeosomes.

(1) Sedlmayr, V. L., Schobesberger, S., Spitz, S., Ertl, P., Wurm, D. J., Quehenberger, J., & Spadiut, O. (2024). Archaeal ether lipids improve internalization and transfection with mRNA lipid nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics, 197, 114213. doi.org

(2) Sedlmayr, V. L., et al. (2026). Beyond PEGylation: Archaeal Lipids for Long-Circulating Liposomes. Advanced NanoBiomed Research, e202500232. doi.org/10.1002/adnb.202500232