Rewiring the mitochondrial NAD+–CoQ axis using metabolic nanomedicine for acute kidney injury therapy

Acute kidney injury (AKI) represents a critical medical condition with high mortality and no effective pharmacotherapy. Mitochondrial dysfunction in proximal tubular epithelial cells (PTECs), characterized by NAD + depletion, CoQ oxidation, and reactive oxygen species (ROS) overproduction, is a central driver of tubular damage and maladaptive repair. As central metabolic molecules, NAD + and CoQ can effectively ameliorate acute kidney injury by alleviating mitochondrial oxidative stress. However, the bioavailability of NAD + is limited by its short half-life, instability, and poor membrane permeability, whereas CoQ, despite being lipophilic, lacks specific mitochondrial targeting, preventing maximal therapeutic efficacy. Here, we report carrier-free NAD + /MitoQH 2 nanoparticles (NM NPs) with ultrasmall size and ROS-responsive properties. NM NPs are designed to pass through the glomerular filtration barrier and preferentially accumulate in injured renal tubules, where they may replenish the NAD + pool and provide a pre-reduced, mitochondria-targeted ubiquinol to support the CoQ axis under oxidative stress. Through renal accumulation and ROS-responsive release, NM NPs showed therapeutic efficacy in hypoxia/reoxygenation- and cisplatin-induced AKI models, as evidenced by reduced ROS accumulation, improved mitochondrial oxidative phosphorylation, enhanced autophagy, and attenuated ferroptosis. This work presents a metabolic nanomedicine strategy based on the co-assembly of bioactive molecules to modulate the mitochondrial NAD + –CoQ axis, providing a promising platform for AKI therapy and potentially other mitochondria-associated diseases.