Neutrophil-Driven Cascade-Targeted Nanocarriers Restore Mitochondrial Homeostasis to Ameliorate Renal Ischemia-Reperfusion Injury

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), with high mortality and a significant risk of progression to chronic kidney disease (CKD). To address the lack of targeted therapies, we developed NKN-LNP, a cascade-targeting drug delivery system that enables spatiotemporally controlled delivery to injured tubules. This system first targets neutrophils via a surface polypeptide, hijacking their inflammatory migration to traverse the glomerular barrier and reach the injury site. Microenvironmental matrix metalloproteinase 2/9 (MMP-2/9) then triggers nanoparticle release, exposing a second peptide that selectively binds to upregulated kidney injury molecule-1 (KIM1) on tubular cells. Loaded with the NAD⁺ precursor β-nicotinamide mononucleotide (NMN), the accumulated NKN-LNP potently activates the NAD⁺-SIRT3 signaling axis, restoring mitochondrial function and ameliorating renal damage in AKI mice. Importantly, this targeted strategy also exerts potent antifibrotic effects, thereby mitigating the AKI-to-CKD transition. This neutrophil-mediated dual-targeting platform offers a promising nanotherapeutic strategy for precise treatment of renal IRI and its chronic progression.