High-Density Lipoprotein Nanoparticles Delivering Liver X Receptor Agonist for the Treatment of Age-Related Macular Degeneration

Liver X nuclear receptor (LXR) agonists are promising therapeutic agents whose efficacy has been demonstrated in vitro and in vivo for the treatment of atherosclerosis. The accumulation of lipids is a common pathogenic mechanism between both atherosclerosis and age-related macular degeneration (AMD). As such, a growing number of studies have implicated LXR agonists as a potential therapeutic option for the treatment of AMD. Unfortunately, the clinical application of LXR agonists has been hindered by their undesirable side effects when administered systemically, as well as their limited aqueous solubility, necessitating a drug delivery system (DDS) for targeted local delivery. Synthetic high-density lipoprotein (sHDL) nanoparticles have intrinsic cholesterol transport and anti-inflammatory functions, making them ideal for the treatment of diseases where cholesterol accumulation and inflammation contribute to the pathology. These nanoparticles also excel as an effective DDS for hydrophobic drugs due to their ability to encapsulate drugs in their hydrophobic core. Thus, we developed a new strategy for AMD treatment by encapsulating an LXR agonist, T0, in sHDL nanoparticles (sHDL-T0). Our in vitro studies showed that sHDL-T0 can effectively upregulate cholesterol transport from mature iPSC-RPE (retinal pigment epithelium) due to increased transcription of cholesterol transporters and by serving as an acceptor for effluxed cholesterol. Encapsulating T0 in sHDL nanoparticles increased the aqueous solubility of T0 significantly, allowing for direct delivery to the eye without organic solvents. In vivo delivery of sHDL-T0 caused upregulation of the Abca1/g1 transporters in the retina and retinal pigment epithelium, suggesting that T0 can escape sHDL nanoparticles and stimulate the LXR pathway. Most importantly, in a murine model of nonexudative (dry) age-related macular degeneration (dAMD), sHDL-T0 administration resulted in the down-regulation of Tnfα, Il-6, and Nlrp3 mRNA expression, and reduced the number of CD45-positive inflammatory cells in comparison to vehicle-treated eyes. Our results provide proof-of-concept for using sHDL nanoparticles to deliver the LXR agonist T0 to restore cholesterol homeostasis and reduce local inflammation in the outer retina, offering a novel therapeutic strategy for dAMD.