Mitochondrial-targeted DNA nanostructures deliver NAD+ to attenuate mitochondrial oxidative injury in renal ischemia-reperfusion.

Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and is associated with substantial morbidity, delayed recovery, and impaired quality of life. Its progression is closely linked to mitochondrial oxidative stress, nicotinamide adenine dinucleotide (NAD+) depletion, and insufficient tubular repair. NAD+ is a key cofactor that sustains mitochondrial bioenergetics and redox homeostasis and supports sirtuin-dependent repair signaling. Therefore, restoring NAD+ metabolism is an attractive therapeutic strategy for IRI. Nevertheless, direct NAD+ administration is limited by poor membrane permeability, rapid metabolic turnover, and insufficient tissue exposure. Tetrahedral DNA nanostructures (TDNs), as programmable and biocompatible DNA nanomaterials, provide an attractive platform for precision drug delivery and chemical functionalization. Here, we constructed TDN-TPP@NAD+, a triphenylphosphonium (TPP)-functionalized TDN carried NAD+ to improve its delivery context in renal IRI. TDN-TPP@NAD+ promoted intracellular delivery of NAD+ in hypoxia-injured HK-2 cells and sustained renal retention after systemic administration. The delivered NAD+ alleviated mitochondrial damage and was associated with restoration of SIRT1-PGC1α-mtTFA signaling, while the TDN scaffold also contributed to the reduction of excessive ROS through its intrinsic antioxidant properties. Thus TDN-TPP@NAD+ reduced tubular pathological injury, and improved renal biochemical indices in vivo. TDN-TPP@NAD+ provides a promising nanotherapeutic strategy for IRI-induced AKI and mitochondrial metabolic disorder-related diseases.