Engineered naringenin-loaded nanoscale coordination polymers for targeted treatment of acute kidney injury.

Acute kidney injury (AKI) is a severe clinical condition lacking targeted and effective pharmacotherapies. Dysregulated inflammation, largely driven by the nuclear factor-κB (NF-κB) signaling pathway, is a primary mediator of tubular damage in AKI. While bioinformatic and preliminary analyses identified the natural flavonoid naringenin (Nag) as a potent NF-κB inhibitor, its therapeutic utility is severely restricted by poor aqueous solubility, rapid systemic metabolism, and insufficient renal accumulation. To address these pharmacokinetic limitations, we synthesized ultra-small (<10 nm) iron-naringenin nanoscale coordination polymers (Fe-Nag NPs). This sub-10 nm design exploits glomerular filtration for passive targeting, specifically leveraging the enhanced vascular permeability of injured kidneys. In both ischemia-reperfusion (IR) and cisplatin-induced murine AKI models, Fe-Nag NPs achieved significantly higher renal drug concentrations compared to free naringenin administration. This targeted delivery substantially improved therapeutic outcomes, as evidenced by restored renal function, attenuated acute histopathological lesions, and the profound suppression of pro-inflammatory cascades. Furthermore, Fe-Nag NPs provided sustained renoprotection, effectively mitigating the functional transition from severe AKI to chronic kidney disease (CKD). By seamlessly integrating transcriptomic insights with functional nanomaterial design, this metal-organic platform not only validates targeted NF-κB inhibition for AKI treatment but also offers a robust strategy for the precise delivery of poorly soluble bioactive natural products.