Targeting Renal IGFBP7 With Tetrahedral Framework Nucleic Acid‐Delivered siRNA Alleviates Acute Kidney Injury

ABSTRACT Acute kidney injury (AKI) is a common and serious clinical condition, yet effective targeted therapies remain lacking. To address this, we developed a tetrahedral framework nucleic acid (tFNA)‐based small interfering RNA (siRNA) delivery system. This system targets renal insulin‐like growth factor‐binding protein 7 (IGFBP7), a crucial predictor and regulatory factor in AKI. By assembling tFNA with siRNA‐IGFBP7 via complementary base pairing, a stable and targeted nanocomplex (tFNA‐siRNA) was constructed. This nanocomplex significantly enhanced siRNA accumulation in the kidneys, particularly in mice subjected to cecal ligation and puncture (CLP) or renal ischemia–reperfusion (I/R). Biocompatibility assays in renal cells and mice both demonstrated that tFNA‐siRNA possessed good biosafety. More importantly, tFNA‐siRNA effectively downregulated IGFBP7 expression and alleviated renal dysfunction and tubular injury in AKI mice, which were subjected to CLP or I/R. Collectively, this study developed a novel gene therapy strategy for AKI and expanded the potential applications of DNA nanomaterials in treating kidney diseases.