Engineering lipid nanostructures for drug delivery and lipid homeostasis

• Applicant: Dr. Kevin Jahnke
• Subject Area: Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564104727

I propose to engineer lipid-based nanostructures, including asymmetric vesicles and synthetic lipid droplets, to investigate the biophysical principles underlying cellular membranes and their implications for drug delivery and lipid homeostasis. By focusing on how nanoscale lipid architectures influence membrane properties, this research seeks to uncover fundamental insights into leaflet asymmetry, vesicle mechanics, and lipid dynamics. Additionally, it aims to develop new technologies for the targeted delivery of ribonucleoprotein complexes and lipids to cells, with the potential to contribute to the advancement of human health. Asymmetric vesicles, with distinct lipid compositions in their inner and outer leaflets, offer a unique platform to investigate biophysical phenomena such as stiffness, fluidity, curvature, and interleaflet coupling. Preliminary findings show that asymmetry enhances vesicle uptake by cells and improves transfection efficiency, even when the outer leaflet remains unchanged. This suggests that the inner leaflet plays an unexpected role in modulating interactions with the cell membrane. This research will systematically investigate how lipid composition and nanoscale asymmetry influence membrane mechanics, uptake, and fusion processes. Synthetic lipid droplets, composed of a hydrophobic core and a lipid monolayer, provide a complementary model to study lipid transport and storage. These droplets mimic cellular lipid reservoirs and offer a means to explore the biophysical properties of lipid-based compartments, such as elasticity, surface tension, and stability. Early results indicate that droplet size influences degradation rates and uptake efficiency, suggesting a biophysical basis for their interaction with cellular machinery. By engineering droplets with controlled size and composition, this project aims to elucidate their roles in lipid homeostasis and membrane dynamics. To bridge nanoscale biophysics with physiological relevance, the project incorporates organ-on-a-chip models to study the behavior of lipid-based nanostructures in three-dimensional environments. These systems allow precise control of flow, tissue architecture, and cell interactions, providing insights into how biophysical properties, such as vesicle stiffness and droplet elasticity, affect penetration, targeting, and uptake. By connecting these findings to organ-level processes, the research aims to reveal how biophysical constraints influence the performance of lipid-based systems in vivo. This work promises to advance our understanding of fundamental membrane biophysics by integrating nanoscale engineering with drug and lipid delivery. By uncovering how lipid asymmetry, compartment architecture, and biophysical properties influence cellular processes, the research has the potential to redefine how we study and manipulate cell membranes, enabling future biotechnological applications.

• DFG Programme: Emmy Noether Independent Junior Research Groups