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

ABSTRACT 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.