The phospholipid composition of artificial lipid droplets enhances their deliverability and facilitates a broad Biodistribution in vivo and in vitro

Artificial lipid droplets (aLDs) provide a useful tool to explore the multiple functionalities of intracellular lipid droplets (LDs). In this study we explored the dynamics and potential multidisciplinary applications of these lipid particles. We have optimised construction of fluorescently labelled aLDs to allow their tracking in various in vitro and in vivo models. Modifying the phospholipid membrane of aLDs achieved enhanced delivery efficiency to a broad range of cells with various origins leading to a wide biodistribution of aLDs to organ systems in both mice and zebrafish models. The broad targeting and stability of this new generation of aLDs holds promise to now utilise aLDs as a novel delivery system as well as offering a toolset for further investigation on intracellular LD dynamics and function. STATEMENT OF SIGNIFICANCE: Artificial lipid droplets (aLDs) are a novel nanoparticle tool for biomedical research, consisting of a phospholipid monolayer with a neutral core interior. They offer new opportunities for the delivery of lipids and proteins in vivo; however, the ability of aLD lipid composition to drive enhanced cellular delivery remains unexplored. Here, we demonstrate that enhancing aLD phospholipid complexity significantly increases in vitro cellular delivery across multiple cell types and offers broad organ biodistribution, including delivery to the brain, in both mice and zebrafish. These findings highlight aLDs as potential vehicles in both basic biological studies and therapeutic interventions. Additionally, increasing the complexity of phospholipids into alternate nanoparticles such as LNPs may enhance organ biodistribution, thus opening the field up to new opportunities for cargo to reach previously undeliverable areas.