Puerarin-loaded hyaluronic acid self-assembled nanoparticles ameliorate hyperuricemic nephropathy by modulating lipid peroxidation and macrophage polarization

Hyperuricemic nephropathy (HUN) is a chronic kidney disease, as featured by the large amount of uric acid (UA) deposited in the kidney. Lipid peroxidation and macrophage infiltration caused by UA are two prominent risk factors linked in the occurrence of HUN. Puerarin (PEA) has anti-hyperuricemia, antioxidant, and anti-inflammatory activity, albeit the poor water solubility and a short half-life limit its application. To improve the bioavailability of PEA, this study prepared PEA-loaded hyaluronic acid (HA) self-assembled nanoparticles (PEA-HA NPs). Release kinetics showed that PEA-HA NPs achieved the pH-responsive sustained-release in the weakly acidic microenvironment of HUN. In vivo biodistribution indicated that PEA-HA NPs was preferably internalized by renal tubular epithelial cells in HUN, which was attributed to the specific binding between HA and CD44 receptor. In vitro health benefits confirmed that PEA-HA NPs modulated lipid peroxidation though a distinctive four-pronged strategy in UA-induced HK-2 cells, including scavenging ROS, restoration of mitochondrial function, regulation of inflammatory pathways, and inhibition of apoapsis. Likewise, PEA-HA NPs could transform the pro-inflammatory macrophages (M1-type) of into anti-inflammatory macrophages (M2-type), thereby inhibiting UA-caused macrophage infiltration. In vivo analysis also showed that PEA-HA NPs could alleviate renal dysfunction and fibrosis by modulating lipid peroxidation and macrophage polarization. This study improves the bioavailability and long-lasting therapeutic duration of PEA, which provides a convenient strategy for the efficient treatment of HUN.