t0901317 and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Topics: Animals; Apoptosis; Autoantibodies; c-Mer Tyrosine Kinase; Cytokines; Disease Progression; Drug Delivery Systems; Drug Evaluation, Preclinical; Female; Gold; Hydrocarbons, Fluorinated; Liposomes; Liver X Receptors; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Nanocapsules; Phosphatidylserines; Sulfonamides; Tissue Distribution

The LXR agonist T0901317 inhibited type I interferon and increased ABCA1 in lupus patients' monocytes and in murine peritoneal macrophages.

Topics: Animals; Cell Polarity; Disease Models, Animal; Hemorrhage; Humans; Hydrocarbons, Fluorinated; Hypoxia-Inducible Factor 1, alpha Subunit; Liver X Receptors; Lupus Erythematosus, Systemic; Macrophages, Peritoneal; Mice; Monocytes; Sulfonamides; Terpenes; Tumor Necrosis Factor-alpha