Biomimetic nanocages with cascade homing for theranostics of ischemia-reperfusion acute kidney injury.
- 1Department of Urology, Pediatric Urolith Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, 310052, China.
- 2Key Laboratory of Oral Biomedical Research of Zhejiang Province, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Hangzhou, 310006, China.
- 3Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital of Jilin University, Changchun, 130021, China.
Abstract
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.
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BibTeX
@article{xu2026biomimetic,
title = {{Biomimetic nanocages with cascade homing for theranostics of ischemia-reperfusion acute kidney injury.}},
author = {Zihao Xu and Yao Wan and Yuhang Shang and Kangjie He and Chao Jiang and Gengyu Du and Yijun Zhao and Qibo Hu and Yang Zhang and Gensheng Zhang and Xiang Yan},
journal = {Materials today. Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103730},
url = {https://europepmc.org/article/MED/42910165},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Biomimetic nanocages with cascade homing for theranostics of ischemia-reperfusion acute kidney injury.
AU - Zihao Xu
AU - Yao Wan
AU - Yuhang Shang
AU - Kangjie He
AU - Chao Jiang
AU - Gengyu Du
AU - Yijun Zhao
AU - Qibo Hu
AU - Yang Zhang
AU - Gensheng Zhang
AU - Xiang Yan
PY - 2026
DA - 2026/10/10
JO - Materials today. Bio
DO - 10.1016/j.mtbio.2026.103730
UR - https://europepmc.org/article/MED/42910165
AB - 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.
SN - 2590-0064
ER -