Kidney-targeting DNA tetrahedral molecular cage synergistically inhibits acute kidney injury by clearing ROS and activating HO-1

Acute kidney injury (AKI) is a major cause of mortality in hospitalized patients, yet effective therapeutic interventions remain underdeveloped. To address this critical need, we have employed tetrahedral framework nucleic acid (tFNA) as a carrier to self-assemble a complex incorporating G-quadruplex and hemin (G4/Hemin). This novel formulation exhibits uniform particle size, targeted delivery, and significant therapeutic efficacy for AKI. In a chemotherapy-induced AKI model, G4/Hemin-tFNA preferentially accumulated in the renal tubules, significantly mitigating drug-induced renal tubular injury. In healthy mice, G4/Hemin-tFNA was rapidly cleared from circulation due to efficient renal filtration. Safety evaluations conducted over a continuous 30-day period indicated minimal side effects associated with G4/Hemin-tFNA administration. Mechanistic studies elucidated three primary molecular mechanisms through which G4/Hemin-tFNA exerts its therapeutic effects in AKI: 1) Enhanced Renal Targeting. G4/Hemin-tFNA facilitates effective renal targeting and protection during blood circulation, leading to significant accumulation of drug within the kidneys. 2) Reactive Oxygen Species (ROS) Clearance. The complex exhibits peroxidase-like activity, enabling the rapid clearance of ROS at the site of AKI lesions, thereby inhibiting the oxidative stress progression. 3) Activation of heme oxygenase-1 (HO-1). G4/Hemin-tFNA selectively activates HO-1, enhancing the concentration of anti-inflammatory factors at inflamed sites and promoting an anti-inflammatory microenvironment. Collectively, these findings demonstrate that G4/Hemin-tFNA is a safe and effective therapeutic agent for AKI. By activating HO-1 and clearing ROS, G4/Hemin-tFNA inhibits disease progression, offering a promising approach for the development of future AKI therapies.