A Universal Framework Nucleic Acid Platform for Kidney-Targeted Delivery of Natural Bioactive Compounds

Natural bioactive compounds (NBCs) possess broad therapeutic potential but face major translational barriers, including poor bioavailability and nonspecific biodistribution. Here, we develop a generic NBC delivery platform using computational virtual screening and tetrahedral framework nucleic acids (tFNA). By integrating molecular docking with experimental validation, we demonstrate that 17 of 30 NBCs can be efficiently loaded onto tFNA via noncovalent DNA-groove binding, providing a universal strategy for assessing FNA-based NBCs loading. As a demonstration, a costunolide (COS)-FNA complex was constructed for acute kidney injury (AKI) therapy. This complex leverages the unique properties of tFNA to achieve rapid renal accumulation (5 min) and prolonged retention (12 h). In AKI mice, COS-FNA showed greatly improved bioavailability and achieved significant therapeutic effects at only 1/300 of the conventional COS dose. This study offers a new therapeutic approach for AKI and a flexible platform for broad clinical delivery of NBCs.