Ultrasmall Polyphenol-NAD + Nanoparticle-Mediated Renal Delivery for Mitochondrial Repair and Anti-Inflammatory Treatment of AKI-to-CKD Progression.

As a central metabolic molecule, nicotinamide adenine dinucleotide (NAD + ) can potentially treat acute kidney injury (AKI) and chronic kidney disease (CKD); however, its bioavailability is poor due to short half-life, instability, the deficiency of targeting, and difficulties in transmembrane transport. Here a physiologically adaptive gallic acid-NAD + nanoparticle is designed, which has ultrasmall size and pH-responsiveness, passes through the glomerular filtration membrane to reach injured renal tubules, and efficiently delivers NAD + into the kidneys. With an effective accumulation in the kidneys, it restores renal function, immune microenvironment homeostasis, and mitochondrial homeostasis of AKI mice via the NAD + -Sirtuin-1 axis, and exerts strong antifibrotic effects on the AKI-to-CKD transition by inhibiting TGF-β signaling. It also exhibits excellent stability, biodegradable, and biocompatible properties, ensuring its long-term safety, practicality, and clinical translational feasibility. The present study shows a potential modality of mitochondrial repair and immunomodulation through nanoagents for the efficient and safe treatment of AKI and CKD.