Date

Wednesday 14 Oct 2026

Time

15:00 - 15:30

Location

BW030

Supervisor

Alexander Kros

2nd reviewer

Sander van Kasteren

Jury

Rolf Boot

Treating glioblastoma requires overcoming one of the most impermeable biological barriers for therapeutic agents: the blood-brain barrier (BBB). The BBB limits glioblastoma treatment by strictly blocking nearly 98% of therapeutic cargos reaching the brain. Lipid nanoparticles (LNPs) have been identified as a promising delivery system for nucleic acid therapeutics. However, conventional LNPs typically possess limited intrinsic brain-targeting capacity and predominantly accumulate in the liver following systemic administration. This thesis investigated neurotransmitter-derived lipid nanoparticles (NT-LNPs) as potential carriers for brain-targeting RNA delivery. Neurotransmitter-inspired ionizable lipids were synthesized, characterized by nuclear magnetic resonance and liquid chromatography-mass spectrometry. These ionizable lipids were used to formulate a NT-LNP library. The LNPs were characterized and their efficacy was tested in vitro. Most formulations produced nanoparticles of approximately 100 nm with PDI values below 0.30, indicating the formation of stable and homogeneous LNPs. Further, RNA was encapsulated efficiently, showing effective RNA loading of the novel ionizable lipids. In vitro transfection experiments revealed efficient nanoparticle internalization across both cell lines bEnd.3 brain endothelial cells and Ink4a Prim glioblastoma-relevant cells. However, uptake did not consistently translate into eGFP expression, indicating that intracellular processing and endosomal escape remained limiting steps for several formulations. Only a subset of formulations produced measurable transgene expressions, particularly the T-LT1, T-LT2, T-LT4 and S-LT1 series in bEnd3 cells and the T-LT1 group in Ink4a cells. These findings highlight the importance of formulation-dependent differences in cytoplasmic cargo release.