Enabling organ- and injury-specific nanocarrier targeting <i>via</i> surface-functionalized PEG- <i>b</i> -PPS micelles for acute kidney injury

While nanomedicine holds great promise for kidney disease, targeted delivery remains a major challenge. Most nanocarriers rely on passive accumulation or epithelial-specific ligands, limiting their utility in complex, inflamed renal environments. In acute kidney injury (AKI), inflammation and vascular dysfunction play central roles, yet targeting strategies beyond the tubule remain underexplored. Here, dual-ligand micelles are developed to enhance nanocarrier localization to the inflamed kidney by simultaneously engaging both organ- and injury-specific cues. Poly(ethylene glycol)-<i>block</i>-poly(propylene sulfide) (PEG-<i>b</i>-PPS) micelles were engineered to display two peptide ligands: CLPVASC, which preferentially distributes to the kidney, and CYNTTTHRC, which binds selectively to inflamed endothelium. These targeting motifs were incorporated <i>via</i> lipid-anchored peptide amphiphiles, enabling modular surface functionalization without disrupting micelle morphology, size, or charge. <i>In vitro</i>, dual-targeted micelles demonstrated enhanced uptake by human endothelial cells exposed to hypoxia-reoxygenation. <i>In vivo</i>, following unilateral renal ischemia-reperfusion injury (IRI) in mice, targeted micelles achieved selective accumulation in the injured kidney, outperforming both non-targeted controls and contralateral kidneys. Off-target distribution to liver, lung, and spleen was markedly reduced, confirming the spatial precision of the dual-ligand approach. This strategy offers a scalable, modular, and biologically informed platform for precision delivery in AKI and related inflammatory conditions.