Improved bioavailability and anti-nephrotoxicity efficacy of polydatin on cisplatin-induced AKI via a dual-targeting fucoidan delivery system

Acute kidney injury (AKI) is a common and serious complication in clinical practice, especially when using chemotherapy drug cisplatin, which severely limits its anti-cancer efficacy. This study developed a novel nano delivery system (Fu-4-PBA/Po NPs) that combines fucoidan (Fu), endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (4-PBA), and natural antioxidant Polydatin (Po) to simultaneously alleviate cisplatin induced oxidative stress and ERS. The optimized Fu-4-PBA/Po NPs showed an average size of 102 ± 3.46 nm, a zeta potential of -16.5 ± 0.49 mV, and a high drug loading capacity of 10.34 ± 0.6 %. They exhibited excellent stability and a sustained release profile <i>in vitro</i>. <i>In vitro</i> results showed that treatment with Fu-4-PBA/Po NPs led to a marked increase in cell survival by 34.73 ± 3.54 percentage points compared to the model group, which had a survival rate of 45.97 ± 2.76 %. Furthermore, Fu-4-PBA/Po NPs effectively inhibited the accumulation of reactive oxygen species (ROS), mitochondrial membrane potential decline, and calcium ion release by targeting P-selectin and endoplasmic reticulum (ER) at the site of inflammation, and significantly alleviate cisplatin induced cell apoptosis. Mechanism studies showed that nanocomposites alleviate ERS by inhibiting the PERK-eIF2α-ATF4-CHOP pathway, while blocking the activation of the cGAS-STING pathway, thereby reducing DNA damage and inflammatory response. Pharmacokinetic studies showed that the peak concentration (Cmax) of the nanoparticles reached 2.2 times that of free Po, and the area under the curve (AUC) increased by 2 times. In animal studies, administration of Fu-4-PBA/Po NPs at a dose of 100 mg/kg notably ameliorated renal function, as indicated by reductions in serum creatinine (SCr) and blood urea nitrogen (BUN) levels by 84.3 % and 62.4 %, respectively, and also improved kidney histopathology. This study provided a dual targeted nano-delivery strategy for cisplatin induced AKI therapy, which has important clinical application potential.