ROS-responsive graphene-hyaluronic acid nanomedicine for targeted therapy in renal ischemia/reperfusion injury

<b>Background</b>: Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD) through the AKI-to-CKD transition; however, effective treatment strategies remain challenging due to the complex and multifactorial pathophysiology of this process. This study aims to develop a multifunctional nanoplatform for kidney-specific targeting, reactive oxygen species (ROS) scavenging, and anti-fibrotic drug delivery to mitigate AKI-to-CKD progression. <b>Methods</b>: Reduced graphene oxide (rGO) was conjugated with hyaluronic acid (HA) to form HA/rGO nanoparticles, enabling CD44-mediated renal targeting and ROS-responsive drug release. Paricalcitol, a hydrophobic anti-fibrotic agent, was loaded onto HA/rGO to form P/HA/rGO. The physicochemical characteristics, ROS-scavenging capacity, and oxidative stress-responsive drug release were evaluated. <i>In vitro</i> cytoprotection was assessed using HK-2 cells under oxidative stress. <i>In vivo</i> studies using ischemia/reperfusion (IR) injury mouse models assessed biodistribution, renal targeting, and therapeutic efficacy after systemic administration of P/HA/rGO. <b>Results</b>: HA/rGO nanoparticles demonstrated potent antioxidant activity and significantly protected HK-2 cells from ROS-induced cytotoxicity. P/HA/rGO exhibited a high paricalcitol loading efficiency (93%) and released 26% of the drug over 30 days under oxidative conditions. P/HA/rGO selectively accumulated in IR-injured kidneys via HA-CD44 interactions, decreased serum NGAL and cystatin C levels, and effectively attenuated tubular injury, fibrosis, inflammation, and apoptosis compared to vehicle-treated controls. <b>Conclusion</b>: The P/HA/rGO nanoplatform enables kidney-targeted delivery of paricalcitol with ROS-scavenging and ROS-responsive release properties, providing a promising therapeutic strategy to suppress the AKI-to-CKD transition via integrated targeting and microenvironment-responsive therapy.