Nanodisc delivery of liver X receptor agonist for the treatment of diabetic nephropathy

Dyslipidemia is recognized to be an important contributor to the progression of diabetic nephropathy (DN), leading to lipoprotein dysregulation, excessive mesangium expansion as well as inflammation in the glomeruli. Thus, dual targeting of abnormal cholesterol metabolism and inflammatory responses of mesangial cells represents an alternative approach for DN treatment. Herein, we sought to develop a renal-targeting therapeutic strategy for diabetic nephropathy by modifying synthetic high-density lipoprotein (sHDL) nanodiscs with a kidney targeting ligand (KT peptide) and encapsulating a liver X receptor (LXR) agonist in the modified sHDL. LXR agonists delivered by sHDL can facilitate the removal of excessive lipids from mesangial cells, ameliorate inflammation and restore normal renal function. Overall, our data suggests that our optimized KT-targeted sHDL/TO nanodiscs (KT-sHDL/TO) generate potent therapeutic efficacy not only by more efficient cholesterol efflux, but also by suppressing mesangial cell proliferation. Most importantly, in a DN murine model, KT-sHDL/TO ameliorated dyslipidemia and inflammation superior to blank sHDL and non-targeting sHDL/TO formulations, showing promise for future clinical translation in DN treatment.