tFNA/GA@siRNOX4: A Multi‐Mechanistic Nanodrug for the Amelioration of Cisplatin‐Induced Acute Kidney Injury

Acute kidney injury (AKI), a life-threatening condition with in-hospital mortality rates up to 50%, is limited by ineffective treatments due to poor delivery and inadequate gene-targeting capability. Herein, we developed an innovative tetrahedral framework nucleic acid-based nanodrug, tFNA/GA@siRNOX4. This nanoplatform has an average hydrodynamic diameter of 7.9 ± 1.35 nm and a ζ-potential of -19.1 ± 1.27 mV. Moreover, tFNA/GA@siRNOX4 exhibited good structural stability and sustained release under physiological conditions, supporting its suitability as a stable and efficient nano-delivery system. This platform enables co-delivery of glycyrrhetinic acid (GA) and siRNA via a "dual-loading single-carrier" strategy. Mechanistically, this system creates a bidirectional therapeutic network by coupling upstream gene silencing with downstream pathway modulation. The rapid delivery of siRNOX4 achieved ∼77% NOX4 knockdown in vitro, effectively reducing reactive oxygen species (ROS) generation at the source. Meanwhile, sustained GA release activates the Nrf2/HO-1 pathway and inhibits NF-κB, cooperatively attenuating oxidative stress and inflammation. In cisplatin-induced AKI models, tFNA/GA@siRNOX4 treatment significantly improved renal function, restored glomerular filtration, and increased the 7-day survival rate from 0% to 80% (with 50% long-term survival). Efficacy was also confirmed in a glycerol-induced AKI model, underscoring its broad therapeutic potential. This study provides a promising therapeutic candidate drug for the treatment of AKI.