<p>Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), yet effective therapeutic strategies remain scarce. Although the natural flavonoid baicalein possesses potential therapeutic properties, its clinical application is limited by suboptimal pharmacokinetic properties such as poor solubility and low stability. To tackle these challenges, we engineered a nanocarrier system utilizing tetrahedral framework nucleic acids (tFNAs) to enhance the delivery and efficacy of baicalein (tFNA-Bai) against renal I/R injury and to investigate its mechanistic basis. The synthesized tFNA-Bai nanoparticles demonstrated uniform size (~ 20&#xa0;nm), sustained release kinetics, and significantly improved serum stability and cellular internalization compared to free baicalein. In renal I/R mouse and cell models, tFNA-Bai afforded superior renoprotection, as indicated by more pronounced improvements in renal function, attenuated histological damage, and reduced cellular apoptosis. Mechanistic investigations integrating network pharmacology and experimental validation revealed that the protective effects were linked to the mitigation of oxidative stress and ferroptosis. Further analysis identified Sirtuin 1 (Sirt1) as a direct target of baicalein. Loss-of-function studies in vivo and in vitro confirmed that Sirt1 is an essential mediator for the antioxidant, anti-ferroptotic, and renoprotective actions of baicalein. In summary, this study introduces an efficient DNA nanostructure-based delivery platform that circumvents the pharmacological limitations of baicalein. Our results demonstrate that the enhanced therapeutic efficacy of tFNA-Bai is largely attributed to the activation of the Sirt1 pathway, which substantially inhibits ferroptosis and oxidative stress in renal I/R injury. This approach offers a novel and promising nanotherapeutic strategy for the treatment of I/R-induced AKI.</p> Graphical abstract <p></p>