Acute kidney injury (AKI) affects an estimated 13 million patients each year with a mortality of up to 1.7 million, yet current clinical management remains largely supportive and lacks etiology-directed therapy. Single-cell transcriptomic analysis revealed that mitochondrial dysfunction in proximal tubular cells is a hallmark of AKI pathology. Inspired by the regenerative capacity of axolotls, which relies on robust mitochondrial bioenergetics, we developed a biomimetic nanoplatform for treating AKI. We engineered GIPL nanoparticles comprising gold-silver nanocages loaded with the mitochondriotropic antioxidant idebenone (IDB), PEGylated for stability, and functionalized with LTH peptide for kidney injury molecule-1 (KIM-1) recognition. This design enables cascade targeting: cell-level targeting via KIM-1-mediated uptake into injured tubular epithelial cells, followed by subcellular accumulation of IDB in mitochondria. In vitro studies demonstrated that GIPL effectively scavenges reactive oxygen species, restores mitochondrial membrane potential, and inhibits apoptosis. Mechanistically, GIPL suppresses mTOR phosphorylation, thereby enhancing mitophagy to clear damaged mitochondria while attenuating pro-apoptotic signaling, ultimately restoring mitochondrial homeostasis. In vivo evaluation in Ischemia-reperfusion (IR) AKI mice confirmed preferential renal accumulation of GIPL, with significant amelioration of tubular injury, oxidative stress, and inflammation. The intrinsic X-ray attenuation of gold-silver nanocages additionally allows renal accumulation of GIPL to be visualized by computed tomography (CT). With a favorable biosafety profile, GIPL is a promising cascade-targeted mitochondrial therapy for IR-AKI. Drawing on the mitochondria-centric regenerative principle of the axolotl, this work integrates single-cell transcriptomic target identification, cascade cell-to-mitochondria delivery, and intrinsic CT contrast into a single nanoplatform, providing a new therapeutic strategy for AKI.
