Neurological conditions are now the leading cause of illness and death in many countries. Their rising prevalence imposes a growing global burden with profound societal and economic impacts. Progress in developing effective therapies for neurodegenerative diseases and brain cancers has lagged behind other medical fields, largely due to the restrictive nature of the blood–brain barrier (BBB). Identifying suitable BBB targets is therefore essential for advancing neurotherapeutic development. One such promising yet underexplored candidate is the choline transporter FLVCR2.
FLVCR2 is highly expressed in brain endothelial cells, where it mediates choline uptake across the BBB. Choline is an essential nutrient required for synthesising phosphatidylcholine—a key cell membrane component—as well as metabolites such as betaine and acetylcholine. Activated choline metabolism is a hallmark of many cancers, including glioblastoma multiforme (GBM), the most aggressive primary brain tumour. Tumour cells display elevated choline demand to support proliferation and malignant transformation, a relationship so strong that choline positron emission tomography is routinely used to diagnose and monitor cancer. Notably, FLVCR2 expression is significantly upregulated in both low-grade glioma and GBM, and higher expression correlates with poorer patient survival. These factors, together with its high BBB localisation, position FLVCR2 as an attractive therapeutic target—both for direct modulation and as a molecular entry point for drug delivery to the brain.
Recent high-resolution cryo-electron microscopy structures of FLVCR2 captured multiple conformations, revealing its mechanism of choline binding and transport. Building on this foundation, this work takes a structure-guided approach to: (i) characterise FLVCR2 substrate promiscuity, (ii) develop selective FLVCR2 inhibitors, and (iii) design FLVCR2-targeting lipid nanoparticles (LNPs) for drug delivery across the BBB. Binding and transport assays using curated libraries of choline-like molecules and the Australian Drug Discovery collection were employed to probe substrate and inhibitor interactions. To enable transporter-mediated transcytosis, FLVCR2-specific antibody fragments were engineered for Fab-LNP targeting. Together, these studies establish a molecular framework for exploiting FLVCR2 both as a therapeutic target and as a gateway for next-generation neurotherapeutics