Dunaliella salina-Loaded Diosmetin Carriers Alleviate Oxidative Stress and Inflammation in Cisplatin-Induced Acute Kidney Injury via PI3K/AKT Pathway

<b>Background:</b> As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae <i>Dunaliella salina</i> (<i>D. salina</i>, <i>Ds</i>) to load Dio (<i>Ds</i>-Dio), thereby enhancing its efficacy and exploring its therapeutic potential. <b>Methods:</b> We first characterized the physicochemical properties of <i>Ds</i> and Dio, and then <i>Ds</i>-Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. <b>Results:</b> The novel <i>Ds</i>-Dio delivery system has been successfully established. In the AKI model, <i>Ds</i>-Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by <i>Ds</i> carrier. In addition, <i>Ds</i>-Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that <i>Ds</i>-Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. <b>Conclusions:</b> This study successfully developed a microalgae-based drug delivery system, <i>Ds</i>-Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation.